Depression is one of the most prevalent and debilitating of the psychiatric disorders. Studies have shown that cognitive therapy is as efficacious as antidepressant medication at treating depression, and it seems to reduce the risk of relapse even after its discontinuation. Cognitive therapy and antidepressant medication probably engage some similar neural mechanisms, as well as mechanisms that are distinctive to each. A precise specification of these mechanisms might one day be used to guide treatment selection and improve outcomes.
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Kessler, R. C. et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R.). JAMA 289, 3095–3105 (2003).
Murray, C. J. L. & Lopez, A. D. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 349, 1436–1442 (1997).
Greenberg, P. E., Burnham, H. G., Lowe, S. W. & Corey-Lisle, P. K. The economic burden of depression in the United States: how did it change from 1990 to 2000? J. Clin. Psychiatry 64, 1465–1475 (2003).
Moussavi, S. et al. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet 370, 851–858 (2007).
DeRubeis, R. J., Young, P. R. & Dahlsgaard, K. K. in Comprehensive clinical psychology Vol. 6 (eds Bellack, A. S. & Hersen, M.) 339–366 (Pergamon, Oxford).
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edn (American Psychiatric Association Press, Washington DC, 2000).
Frank, E. et al. Conceptualization and rationale for consensus definitions of terms in major depressive disorder: remission, recovery, relapse, and recurrence. Arch. Gen. Psychiatry 48, 851–855 (1991).
de Mello, M. F., de Jesus Mari, J., Bacaltchuk, J., Verdeli, H. & Neugebauer, R. A systematic review of research findings on the efficacy of interpersonal therapy for depressive disorders. Eur. Arch. Psychiatry Clin. Neurosci. 255, 75–82 (2005).
UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet 361, 799–808 (2003).
Nahas, Z., et al. Two-year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes. J. Clin. Psychiatry 66, 1097–1104 (2005).
Dimidjian, S. et al. Behavioral activation, cognitive therapy, and anti-depressant medication in the acute treatment of major depression. J. Consult. Clin. Psychol. 74, 658–670 (2006).
Hammond, D. C. Neurofeedback with anxiety and affective disorders. Child. Adolesc. Psychiatr. Clin. N. Am. 14, 105–123 (2005).
Baehr, E., Rosenfeld, J. P. & Baehr, R. The clinical use of an alpha asymmetry protocol in the neurofeedback treatment of depression: Two case studies. J. Neurotherapy 2, 10–23 (1997).
Mayberg, H. S. et al. Deep brain stimulation for treatment-resistant depression. Neuron 45, 651–660 (2005).
Depression Guideline Panel. Depression in Primary Care Vol. 2: Treatment of Major Depression (Clinical Practice Guideline No 5; AHCPR Publ. No 93–0551) (US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, Rockville, Maryland, 1993).
Agency for Health Care Policy and Research. Treatment of depression – newer pharmacotherapies. Summary; Evidence report/technology assessment: number 7. US Department of Health and Human Services [online] (1999).
Thase, M. E. & Rush, A. J. When at first you don't succeed...sequential strategies for antidepressant nonresponders. J. Clin. Psychiatry 58 (Suppl. 13), 23–29 (1997).
Hollon, S. D., Thase, M. E. & Markowitz, J. C. Treatment and prevention of depression. Psychol. Sci. Public Interest 3, 39–77 (2002).
American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am. J. Psychiatry 157 (suppl. 4), 1–45 (2000).
Sheline, Y. I. et al. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol. Psychiatry 50, 651–658 (2001).
Warner-Schmidt, J. L. & Duman, R. S. Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment. Hippocampus 16, 239–249 (2006).
Beck, A. T., Rush, A. J., Shaw, B. F. & Emery, G. Cognitive therapy of depression (Guilford, New York, 1979).
Rush, A. J., Beck, A. T., Kovacs, M. & Hollon, S. D. Comparative efficacy of cognitive therapy and pharmacotherapy in the treatment of depressed outpatients. Cognit. Ther. Res. 1, 17–38 (1977).
Blackburn, I. M., Bishop, S., Glen, A. I. M., Whalley, L. J. & Christie, J. E. The efficacy of cognitive therapy in depression: a treatment trial using cognitive therapy and pharmacotherapy, each alone and in combination. Br. J. Psychiatry 139, 181–189 (1981).
Murphy, G. E., Simons, A. D., Wetzel, R. D. & Lustman, P. J. Cognitive therapy and pharmacotherapy, singly and together, in the treatment of depression. Arch. Gen. Psychiatry 41, 33–41 (1984).
Hollon, S. D. et al. Cognitive therapy, pharmacotherapy and combined cognitive-pharmacotherapy in the treatment of depression. Arch. Gen. Psychiatry 49, 774–781 (1992).
Kovacs, M., Rush, A. T., Beck, A. T. & Hollon, S. D. Depressed outpatients treated with cognitive therapy or pharmacotherapy: a one-year follow-up. Arch. Gen. Psychiatry 38, 33–39 (1981).
Blackburn, I. M., Eunson, K. M. & Bishop, S. A two year naturalistic follow up of depressed patients treated with cognitive therapy, pharmacotherapy and a combination of both. J. Affect. Disord. 10, 67–75 (1986).
Simons, A. D., Murphy, G. E., Levine, J. L. & Wetzel, R. D. Cognitive therapy and pharmacotherapy for depression: sustained improvement over one year. Arch. Gen. Psychiatry 43, 43–48 (1986).
Evans, M. D. et al. Differential relapse following cognitive therapy, pharmacotherapy, and combined cognitive-pharmacotherapy for depression. Arch. Gen. Psychiatry 49, 802–808 (1992).
Elkin, I. et al. Initial severity and differential treatment outcome in the National Institute of Mental Health Treatment of Depression Collaborative Research Program. J. Consult. Clin. Psychol. 63, 841–847 (1995).
Shea, M. T. et al. Course of depressive symptoms over follow-up: findings from the National Institute of Mental Health Treatment of Depression Collaborative Research Program. Arch. Gen. Psychiatry 49, 782–787 (1992).
Jacobson, N. S. & Hollon, S. D. Prospects for future comparisons between drugs and psychotherapy: lessons from the CBT-versus-pharmacotherapy exchange. J. Consult. Clin. Psychol. 64, 104–108 (1996).
DeRubeis, R. J., Gelfand, L. A., Tang, T. Z. & Simons, A. D. Medications versus cognitive behavioral therapy for severely depressed outpatients: mega-analysis of four randomized comparisons. Am. J. Psychiatry 156, 1007–1013 (1999).
DeRubeis, R. J. et al. Cognitive therapy vs. medications in the treatment of moderate to severe depression. Arch. Gen. Psychiatry 62, 409–416 (2005).
Bhar, S. S. et al. Sequence of improvement in depressive symptoms across cognitive therapy and pharmacotherapy. J. Affect. Disord. 110, 161–166 (2008).
DiMascio, A. et al. Differential symptom reduction by drugs and psychotherapy in acute depression. Arch. Gen. Psychiatry 36, 1450–1456 (1979).
Hollon, S. D. et al. Prevention of relapse following cognitive therapy vs medications in moderate to severe depression. Arch. Gen. Psychiatry 62, 417–422 (2005).
Ramel, W. et al. Amygdala reactivity and mood-congruent memory in individuals at risk for depressive relapse. Biol. Psychiatry 61, 231–239 (2007).
Liotti, M., Mayberg, H. S., McGinnis, S. Brannan, S. L. & Jerabek, P. Unmasking disease-specific cerebral blood flow abnormalities: mood challenge in patients with remitted unipolar depression. Am. J. Psychiatry 159, 1830–1840 (2002).
LeDoux, J. The Emotional Brain (Schuster, New York, 1996).
Sheline, Y. I., Sanghavi, M., Mintun, M. A. & Gado, M. H. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression J. Neuroscience 19, 5034–5043 (1999).
Abercrombie, H. et al. Metabolic rate in the right amygdala predicts negative affect in depressed patients. Neuroreport 9, 3301–3307 (1998).
Siegle, G. J., Steinhauer, S. R., Thase, M. E., Stenger, V. A. & Carter, C. S. Can't shake that feeling: fMRI assessment of sustained amygdala activity in response to emotional information in depressed individuals. Biol. Psychiatry 51, 693–707 (2002).
Drevets, W. C. Prefrontal cortical amygdalar metabolism in major depression. Ann. NY Acad. Sci. 877, 614–637 (1999).
Siegle, G. J., Thompson, W., Carter, C. S., Steinhauer, S. R. & Thase, M. E. Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biol. Psychiatry 61, 198–209 (2007).
Dougherty, D. & Rauch, S. Neuroimaging and neurobiological models of depression. Harv. Rev. Psychiatry 5, 138–159 (1997).
Evans, K. C. et al. A functional MRI study of amygdala responses to angry schematic faces in social anxiety disorder. Depress. Anxiety 25, 496–505 (2007).
Metcalfe, J. & Mischel, W. A hot/cool-system analysis of delay of gratification: dynamics of willpower. Psychol. Rev. 106, 3–19 (1999).
Davidson, R. J. Affective style psychopathology and resilience: brain mechanisms and plasticity. Am. Psychol. 55, 1196–1214 (2000).
Drevets, W. C. & Raichle, M. Reciprocal suppression of regional cerebral blood flow during emotional versus higher cognitive processes: implications for interactions between emotion and cognition. Cogn. Emot. 12, 353–385 (1998).
Mayberg, H. S. et al. Reciprocal limbic cortical function and negative mood: converging PET findings in depression and normal sadness. Am. J. Psychiatry 156, 675–682 (1999).
Ochsner, K. N., Bunge, S. A., Gross, J. J. & Gabrieli, J. D. E. Rethinking feelings: an fMRI study of the cognitive regulation of emotion. J. Cogn. Neurosci. 14, 1215–1229 (2002).
Ochsner, K. et al. For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. Neuroimage 23, 483–499 (2004).
Ray, J. P. & Price, J. L. The organization of projections from the mediodorsal nucleus of the thalamus to orbital and medial prefrontal cortex in macaque monkeys. J. Comp. Neurol. 337, 1–31 (1993).
Ghashghaei, H. T. & Barbas, H. Pathways for emotion: interactions of prefrontal and anterior temporal pathways in the amygdala of the rhesus monkey. Neuroscience 115, 1261–1279 (2002).
Mayberg, H. S. Limbic-cortical dysregulation: a proposed model of depression. J. Neuropsychiatry Clin. Neurosci. 9, 471–481 (1997).
Drevets, W. C. Neuroimaging studies of mood disorders. Biol. Psychiatry 48, 813–829 (2000).
Carter, C. S. et al. Parsing executive processes: strategic vs evaluative functions of the anterior cingulate cortex. Proc. Natl Acad. Sci. USA 97, 1944–1948 (2000).
Davidson, R. J. Affective neuroscience and psychophysiology: toward a synthesis. Psychophysiology 40, 655–665 (2003).
Phillips, M. L., Ladouceur, C. D. & Drevets, W. C. A neural model of voluntary and automatic emotion regulation: implications for understanding the pathophysiology and neurodevelopment of bipolar disorder. Mol. Psychiatry 24 Jun 2008 (doi: 10.1038/mp.2008.65).
Beck, A. T. The evolution of the cognitive model of depression and its neurobiological correlates. Am. J. Psychiatry 165, 969–977 (2008).
Davidson, R. J. Assymetric brain function affective style and psychopathology: the role of early experience and plasticity. Dev. Psychopathol. 6, 741–758 (1994).
Baxter, L. et al. Reduction of prefrontal glucose metabolism common to three types of depression. Arch. Gen. Psychiatry 46, 243–250 (1989).
Bench, C. J., Friston, K. J., Brown, R. G., Frackowiak, R. S. & Dolan, R. J. Regional cerebral blood flow in depression measured by positron emission tomography: the relationship with clinical dimensions. Psychol. Med. 23, 579–590 (1993).
Ottowitz, W. E., Dougherty, D. D. & Savage, C. R. The neural network basis for abnormalities of attention and executive function in major depressive disorder: implications for application of the medical disease model to psychiatric disorders. Harv. Rev. Psychiatry 10, 86–99 (2002).
Liotti, M. & Mayberg, H. S. The role of functional neuroimaging in the neuropsychology of depression. J. Clin. Exp. Neuropsychol. 23, 121–136 (2001).
Cohen, J. D. et al. Temporal dynamics of brain activation during a working memory task. Nature 386, 604–608 (1997).
Harvey, P. O. et al. Executive functions and updating of the contents of working memory in unipolar depression. J. Psychiatr. Res. 38, 567–576 (2004).
Egeland, J. et al. Attention profile in schizophrenia compared with depression: differential effects of processing speed, selective attention and vigilance. Acta Psychiatr. Scand. 108, 276–284 (2003).
Watkins, E. & Brown, R. G. Rumination and executive function in depression: an experimental study. J. Neurol. Neurosurg. Psychiatry 72, 400–402 (2002).
Phillips, M. L., Drevets, W. C., Rauch, S. L. & Lane, R. Neurobiology of emotion perception II: implications for major psychiatric disorders. Biol. Psychiatry 54, 515–528 (2003).
Charney, D. S. Monoamine dysfunction and the pathophysiology and treatment of depression. J. Clin. Psychiatry 59 (Suppl. 14), 11–14 (1998).
Mayberg, H. S. Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. Br. Med. Bull. 65, 193–207 (2003).
Seminowicz, D. A. et al. Limbic-frontal circuitry in major depression: a path modeling metanalysis. Neuroimage 22, 409–418 (2004).
Mayberg, H. S. Positron emission tomography imaging in depression: a neural systems perspective. Neuroimaging Clin. N. Am. 13, 805–815 (2003).
Ingram, R. E. & Hollon, S. D. Information Processing Approaches to Clinical Psychology (ed. Ingram, R. E.) 261–284 (Academic, New York, 1986).
Ohira, H. et al. Association of neural and physiological responses during voluntary emotion suppression. Neuroimage 29, 721–733 (2006).
O'Reardon, J. P. et al. Prefrontal-amygdala interactions and mood regulation: a perfusion fMRI study. Brain Cogn. 51, 185 (2003).
Ray, R. D. et al. Individual differences in trait rumination and the neural systems supporting cognitive reappraisal. Cogn. Affect Behav. Neurosci. 5, 156–168 (2005).
Rush, A. J., Beck, A. T., Kovacs, M., Weissenburger, J. & Hollon, S. D. Comparison of the effects of cognitive therapy and pharmacotherapy on hopelessness and self-concept. Am. J. Psychiatry 139, 862–866 (1982).
Blackburn, I. M. & Bishop, S. Changes in cognition with pharmacotherapy and cognitive therapy. Br. J. Psychiatry 143, 609–617 (1983).
Garamoni, G. L., Reynolds, C. F., Thase, M. E., Frank, E. & Fasiczka, A. L. Shifts in affective balance during cognitive therapy of major depression. J. Consult. Clin. Psychol. 60, 260–266 (1992).
DeRubeis, R. J. et al. How does cognitive therapy work? Cognitive change and symptom change in cognitive therapy and pharmacotherapy for depression. J. Consult. Clin. Psychol. 58, 862–869 (1990).
Siegle, G. J., Carter, C. S. & Thase, M. E. Use of fMRI to predict recovery from unipolar depression with cognitive behavior therapy. Am. J. Psychiatry 163, 735–738 (2006).
Siegle, G. J., Thompson, W., Horner, M. S., Carter, C. S. & Thase, M. E. in Executive function: from basic research to clinical practice. Symp. Meet. Assoc. Behav. Cogn. Ther. (Philadelphia, Pennsylvania, 2007).
Straube, T., Glauer, M., Dilger, S., Mentzel, H. J. & Miltner, W. H. Effects of cognitive-behavioral therapy on brain activation in specific phobia. Neuroimage 29, 125–135 (2006).
Paquette, V. et al. “Change the mind and you change the brain”: effects of cognitive-behavioral therapy on the neural correlates of spider phobia. Neuroimage 18, 401–409 (2003).
Siegle, G. J., Ghinassi, F. & Thase, M. E. Neurobehavioral therapies in the 21st century: summary of an emerging field and an extended example of Cognitive Control Training for depression. Cogn. Ther. Res. 31, 235–262 (2007).
Goldapple, K. et al. Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy. Arch. Gen. Psychiatry 61, 34–41 (2004).
Saxena, S. et al. Differential cerebral metabolic changes with paroxetine treatment of obsessive-compulsive disorder vs major depression. Arch. Gen. Psychiatry 59, 250–261 (2002).
Brody, A. L. et al. Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine. Psychiatry Res. 91, 127–139 (1999).
Brody, A. L. et al. Brain metabolic changes associated with symptom factor improvement in major depressive disorder. Biol. Psychiatry 50, 171–178 (2001).
Brody, A. L. et al. Regional brain metabolic changes in patients with major depression treated with either paroxetine or interpersonal therapy: preliminary findings. Arch. Gen. Psychiatry 58, 631–640 (2001).
Kennedy, S. H. et al. Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression. Am. J. Psychiatry 158, 899–905 (2001).
Mayberg, H. S. et al. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol. Psychiatry 48, 830–843 (2000).
Buchsbaum, M. S. et al. Effect of sertraline on regional metabolic rate in patients with affective disorder . Biol. Psychiatry 41, 15–22 (1997).
Nobler, M. S., Olvet, K. R. & Sackeim, H. A. Effects of medications on cerebral blood flow in late-life depression. Curr. Psychiatry Rep. 4, 51–58 (2002).
Fu, C. H. et al. Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study. Arch. Gen. Psychiatry 61, 877–889 (2004).
Davidson, R. J., Irwin, W., Anderle, M. J. & Kalin, N. H. The neural substrates of affective processing in depressed patients treated with venlafaxine. Am. J. Psychiatry 160, 64–75 (2003).
Hollon, S. D., Evans, M. D. & DeRubeis, R. J. in Contemporary Psychological Approaches to Depression: Theory, Research, and Treatment (ed. Ingram, R.) 117–136 (Plenum, New York, 1990).
Brody, A. L. et al. FDG-PET predictors of response to behavioral therapy and pharmacotherapy in obsessive compulsive disorder. Psychiatry Res. 84, 1–6 (1998).
Urry, H. L. et al. Amygdala and ventromedial prefrontal cortex are inversely coupled during regulation of negative affect and predict the diurnal pattern of cortisol secretion among older adults. J. Neurosci. 26, 4415–4425 (2006).
Anand, A. et al. Antidepressant effect on connectivity of the mood-regulating circuit: an fMRI study. Neuropsychopharmacology 30, 1334–1344 (2005).
Canli, T. et al. Amygdala reactivity to emotional faces predicts improvement in major depression. Neuroreport 16, 1267–1270 (2005).
McClure, E. B. et al. fMRI predictors of treatment outcome in pediatric anxiety disorders. Psychopharmacology (Berl.) 191, 97–105 (2007).
Fu, C. H. et al. Neural responses to sad facial expressions in major depression following cognitive behavioral therapy. Biol. Psychiatry 10 Jun 2008 (doi:10.1016/j.biopsych.2008.04.033).
Mayberg, H. S. et al. Cingulate function in depression: a potential predictor of treatment response. Neuroreport 8, 1057–1061 (1997).
Pizzagalli, D. et al. Anterior cingulate activity as a predictor of degree of treatment response in major depression: evidence from brain electrical tomography analysis. Am. J. Psychiatry 158, 405–415 (2001).
Chen, C. H. et al. Brain imaging correlates of depressive symptom severity and predictors of symptom improvement after antidepressant treatment. Biol. Psychiatry 62, 407–414 (2007).
McCullough, J. P. Treatment for Chronic Depression: Cognitive Behavioral Analysis System of Psychotherapy (CBASP). (Guilford, New York, 2003).
Nemeroff, C. B. et al. Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma. Proc. Natl Acad. Sci. USA 100, 14293–14296 (2003).
Hayden, E. P. et al. Early-emerging cognitive vulnerability to depression and the serotonin transporter promoter region polymorphism. J. Affect. Dis. 107, 227–230 (2008).
Kazdin, A. E. Developing a research agenda for child adolescent psychotherapy. Arch. Gen. Psychiatry 57, 829–840 (2000).
Hollon, S. D., DeRubeis, R. J. & Evans, M. D. Causal mediation of change in treatment for depression: discriminating between nonspecificity and noncausality. Psychol. Bull. 102, 139–149 (1987).
Barber, J. P. & DeRubeis, R. J. On second thought: where the action is in cognitive therapy for depression. Cognit. Ther. Res. 13, 441–457 (1989).
Supported by grants MH50129 and MH60998 (R.J.DR.), MH55875, MH060713 and MH01697 (S.D.H.) and MH074807 and MH082998 (G.J.S.) from the National Institute of Mental Health.
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DeRubeis, R., Siegle, G. & Hollon, S. Cognitive therapy versus medication for depression: treatment outcomes and neural mechanisms. Nat Rev Neurosci 9, 788–796 (2008). https://doi.org/10.1038/nrn2345
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