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Editorial   |    
The Emerging Role of Neuroimaging in Psychiatry: Characterizing Treatment-Relevant Endophenotypes
Mary L. Phillips, M.D.
Am J Psychiatry 2007;164:697-699. doi:10.1176/appi.ajp.164.5.697

The research agenda for DSM-V emphasizes a need to translate basic and clinical neuroscience research findings into a new classification system for all psychiatric disorders based upon pathophysiologic and etiological processes (1–4). It is becoming increasingly clear, however, that we need to move toward identifying endophenotypes that not only reflect underlying pathophysiologic processes specific to a disorder but that also mediate response to specific treatments to help guide our treatment choice for individuals as early as possible in their illness course.

In this issue of the Journal, three articles highlight the need in psychiatry for improved means of identifying as early as possible subgroups of individuals with a given psychiatric disorder who will respond preferentially to a specific treatment. Two of these articles demonstrate that neuroimaging techniques may provide a methodology to help us achieve this ultimate goal.

In one article, Frank et al. present data identifying a subgroup of individuals from a larger group of 233 female adults with unipolar depression who were able to achieve remission with interpersonal therapy alone and for whom maintenance interpersonal therapy, even at a frequency of only one visit per month, was a good method of prophylaxis. In contrast, they show that for women who required the addition of pharmacotherapy to achieve remission, interpersonal therapy monotherapy was a significantly less efficacious maintenance treatment. A key concluding point the authors make is that while they were able retrospectively to identify the subgroup of women who responded well to both acute and maintenance interpersonal therapy, none of the traditional measures of depression severity or other parameters of illness distinguished that subgroup from those who required the combination therapy to achieve and maintain remission. They argue for “new ways of distinguishing the various phenotypes of unipolar disorder for which treatment requirements differ.”

In a second article in this issue of the Journal, Kennedy et al. present the first study to examine in unipolar depression patients abnormalities in neural systems that mediate response to two contrasting interventions for unipolar depression: venlafaxine and cognitive behavior therapy (CBT). Both venlafaxine (N=12) and CBT (N=12) were administered as monotherapy to a group of adults with unipolar depression in the context of an extended 16-week randomized comparative trial. Using fluorine-18-fluorodeoxyglucose positron emission tomography to measure cerebral glucose metabolism, the authors show in treatment responders three broad patterns of changes in cerebral metabolism in corticolimbic regions associated with mood and emotion regulation (5). These include 1) changes common to both CBT and venlafaxine responders, 2) opposite patterns of change in responders to each intervention, and 3) changes unique to each intervention. They were also able to determine changes that identified nonresponders to each treatment. This study builds on existing data indicating “differential changes in regional brain activity following response (and nonresponse) to pharmacotherapy compared with psychotherapy” (6–12) but is the first to make a direct comparison between changes in neural activity associated with these two treatment modalities in the context of a randomized controlled trial.

There are limitations to this study, including the relatively small cohort size, the generalizability of findings to real-world populations of depressed patients, and the acquisition of resting-state rather than emotion or cognitive challenge neuroimaging scans. As the authors point out, their findings lead directly to consideration of a crucially important area of psychiatric neuroimaging research, namely, the feasibility of identifying neuroimaging predictors of treatment response in unipolar depression. They argue that examination of baseline, pretreatment patterns of cerebral metabolism may help identify those individuals who subsequently respond best to each intervention. This emerging area of neuroimaging research has the potential to fulfill the ultimate goal of identifying treatment-relevant endophenotypes, not only in unipolar depression but in all major psychiatric disorders.

In a timely brief report, Ma et al. present data that indicate pretreatment abnormalities in neural circuitry underlying mood regulation in 14 young adults with unipolar depression. In the first diffusion tensor imaging study of treatment-naive young adults with unipolar depression, the authors show that abnormalities of white matter are present early in the course of illness in four regions, including a prefrontal cortical region linked with mood regulation and cognitive control similar in nature to one of the regions identified by Kennedy et al. While this is a relatively small study, the findings indicate the feasibility of employing diffusion tensor imaging and, indeed, other neuroimaging modalities, not only to identify abnormalities that exist before treatment in neural systems in individuals with psychiatric disorders but also those abnormalities that may predict subsequent clinical course and treatment response.

Can neuroimaging really help us achieve the goal of identifying treatment-relevant endophenotypes in unipolar depression or, indeed, other psychiatric disorders? First, we have evidence demonstrating the feasibility of neuroimaging techniques in helping to identify neural system abnormalities that mediate clinical change in unipolar depression. We then have further evidence that neuroimaging techniques can identify pretreatment abnormalities in neural systems important for mood regulation that closely overlap in nature with neural system abnormalities shown to mediate treatment response in unipolar depression.

Do different types of pretreatment neural system abnormalities in individuals with psychiatric illness characterize subsequent treatment response? Emerging data from preliminary neuroimaging studies suggest so (13, 14). We are surely now in a position in psychiatry to fully embrace the potential of neuroimaging and other basic and clinical neuroscience findings to help us identify neural system abnormalities that are more accurate than traditional clinical measures in characterizing subgroups of individuals who will subsequently respond best to different treatment modalities.

1.Charney DS, Barlow DH, Botterton K, Cohen JD, Goldman D, Gur RE, Lin K-M, Lopez JF, Meador-Woodruff JH, Moldin SO, Nestler EJ, Waton SJ, Zalcman SJ: Neuroscience research agenda to guide development of a pathophysiologically based classification system, in A Research Agenda for DSM-V. Edited by Kupfer DJ, First MB, Regier DA. Arlington, Va, American Psychiatric Publishing, 2002
 
2.Hasler G, Drevets WC, Gould TD, Gottesman II, Manji HK: Toward constructing an endophenotype strategy for bipolar disorders. Biol Psychiatry 2006; 60:93–105
 
3.Hasler G, Drevets WC, Manji HK, Charney DS: Discovering endophenotypes for major depression. Neuropsychopharmacology 2004; 29:1765–1781
 
4.Phillips ML, Frank E: Redefining bipolar disorder: toward DSM-V. Am J Psychiatry 2006; 163:1135–1136
 
5.Phillips ML, Drevets WC, Rauch SL, Lane RD: The neurobiology of emotion perception, I: towards an understanding of the neural basis of normal emotion perception. Biol Psychiatry 2003; 54:504–514
 
6.Brody AL, Saxena S, Silverman DH, Alborzian S, Fairbanks LA, Phelps ME, Huang SC, Wu HM, Maidment K, Baxter LR Jr: Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine. Psychiatry Res 1999; 91:127–139
 
7.Goldapple K, Segal Z, Garson C, Lau M, Bieling P, Kennedy S, Mayberg H: Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy. Arch Gen Psychiatry 2004; 61:34–41
 
8.Holthoff VA, Beuthien-Baumann B, Zundorf G, Triemer A, Ludecke S, Winiecki P, Koch R, Fuchtner F, Herholz K: Changes in brain metabolism associated with remission in unipolar major depression. Acta Psychiatr Scand 2004; 110:184–194
 
9.Kennedy SH, Evans KR, Kruger S, Mayberg HS, Meyer JH, McCann S, Arifuzzman AI, Houle S, Vaccarino FJ: Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression. Am J Psychiatry 2001; 158:899–905
 
10.Little JT, Ketter TA, Kimbrell TA, Dunn RT, Benson BE, Willis MW, Luckenbaugh DA, Post RM: Bupropion and venlafaxine responders differ in pretreatment regional cerebral metabolism in unipolar depression. Biol Psychiatry 2005; 57:220–228
 
11.Martin SD, Martin E, Rai SS, Richardson MA, Royall R: Brain blood flow changes in depressed patients treated with interpersonal psychotherapy or venlafaxine hydrochloride: preliminary findings. Arch Gen Psychiatry 2001; 58:641–648
 
12.Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA: Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 2000; 48:830–843
 
13.Mayberg HS, Brannan SK, Mahurin RK, Jerabek PA, Brickman JS, Tekell JL, Silva JA, McGinnis S, Glass TG, Martin CC, Fox PT: Cingulate function in depression: a potential predictor of treatment response. Neuroreport 1997; 8:1057–1061
 
14.Siegle GJ, Carter CS, Thase ME: Use of fMRI to predict recovery from unipolar depression with cognitive behavior therapy. Am J Psychiatry 2006; 163:735–738
 

Address correspondence and reprint requests to Dr. Phillips, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Loeffler Building, 121 Meyran Avenue, Pittsburgh, PA 15213; phillipsml@upmc.edu (e-mail).

Dr. Phillips is the NARSAD Nellie Blumenthal Investigator.

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References

1.Charney DS, Barlow DH, Botterton K, Cohen JD, Goldman D, Gur RE, Lin K-M, Lopez JF, Meador-Woodruff JH, Moldin SO, Nestler EJ, Waton SJ, Zalcman SJ: Neuroscience research agenda to guide development of a pathophysiologically based classification system, in A Research Agenda for DSM-V. Edited by Kupfer DJ, First MB, Regier DA. Arlington, Va, American Psychiatric Publishing, 2002
 
2.Hasler G, Drevets WC, Gould TD, Gottesman II, Manji HK: Toward constructing an endophenotype strategy for bipolar disorders. Biol Psychiatry 2006; 60:93–105
 
3.Hasler G, Drevets WC, Manji HK, Charney DS: Discovering endophenotypes for major depression. Neuropsychopharmacology 2004; 29:1765–1781
 
4.Phillips ML, Frank E: Redefining bipolar disorder: toward DSM-V. Am J Psychiatry 2006; 163:1135–1136
 
5.Phillips ML, Drevets WC, Rauch SL, Lane RD: The neurobiology of emotion perception, I: towards an understanding of the neural basis of normal emotion perception. Biol Psychiatry 2003; 54:504–514
 
6.Brody AL, Saxena S, Silverman DH, Alborzian S, Fairbanks LA, Phelps ME, Huang SC, Wu HM, Maidment K, Baxter LR Jr: Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine. Psychiatry Res 1999; 91:127–139
 
7.Goldapple K, Segal Z, Garson C, Lau M, Bieling P, Kennedy S, Mayberg H: Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy. Arch Gen Psychiatry 2004; 61:34–41
 
8.Holthoff VA, Beuthien-Baumann B, Zundorf G, Triemer A, Ludecke S, Winiecki P, Koch R, Fuchtner F, Herholz K: Changes in brain metabolism associated with remission in unipolar major depression. Acta Psychiatr Scand 2004; 110:184–194
 
9.Kennedy SH, Evans KR, Kruger S, Mayberg HS, Meyer JH, McCann S, Arifuzzman AI, Houle S, Vaccarino FJ: Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression. Am J Psychiatry 2001; 158:899–905
 
10.Little JT, Ketter TA, Kimbrell TA, Dunn RT, Benson BE, Willis MW, Luckenbaugh DA, Post RM: Bupropion and venlafaxine responders differ in pretreatment regional cerebral metabolism in unipolar depression. Biol Psychiatry 2005; 57:220–228
 
11.Martin SD, Martin E, Rai SS, Richardson MA, Royall R: Brain blood flow changes in depressed patients treated with interpersonal psychotherapy or venlafaxine hydrochloride: preliminary findings. Arch Gen Psychiatry 2001; 58:641–648
 
12.Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA: Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 2000; 48:830–843
 
13.Mayberg HS, Brannan SK, Mahurin RK, Jerabek PA, Brickman JS, Tekell JL, Silva JA, McGinnis S, Glass TG, Martin CC, Fox PT: Cingulate function in depression: a potential predictor of treatment response. Neuroreport 1997; 8:1057–1061
 
14.Siegle GJ, Carter CS, Thase ME: Use of fMRI to predict recovery from unipolar depression with cognitive behavior therapy. Am J Psychiatry 2006; 163:735–738
 
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