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Original Investigation |

Toward a Neuroimaging Treatment Selection Biomarker for Major Depressive Disorder

Callie L. McGrath, BA1,2; Mary E. Kelley, PhD3; Paul E. Holtzheimer III, MD5; Boadie W. Dunlop, MD1; W. Edward Craighead, PhD1; Alexandre R. Franco, PhD6; R. Cameron Craddock, PhD7,8; Helen S. Mayberg, MD1,4
[+] Author Affiliations
1Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia
2Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, Georgia
3Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia
4Department of Neurology, Emory University, Atlanta, Georgia
5Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
6Department of Electrical Engineering and Brain Institute, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil
7Center for the Developing Brain, Child Mind Institute, New York, New York
8Nathan Kline Institute for Psychiatric Research, Orangeburg, New York
JAMA Psychiatry. 2013;70(8):821-829. doi:10.1001/jamapsychiatry.2013.143.
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Importance  Currently, fewer than 40% of patients treated for major depressive disorder achieve remission with initial treatment. Identification of a biological marker that might improve these odds could have significant health and economic impact.

Objective  To identify a candidate neuroimaging “treatment-specific biomarker” that predicts differential outcome to either medication or psychotherapy.

Design  Brain glucose metabolism was measured with positron emission tomography prior to treatment randomization to either escitalopram oxalate or cognitive behavior therapy for 12 weeks. Patients who did not remit on completion of their phase 1 treatment were offered enrollment in phase 2 comprising an additional 12 weeks of treatment with combination escitalopram and cognitive behavior therapy.

Setting  Mood and anxiety disorders research program at an academic medical center.

Participants  Men and women aged 18 to 60 years with currently untreated major depressive disorder.

Intervention  Randomized assignment to 12 weeks of treatment with either escitalopram oxalate (10-20 mg/d) or 16 sessions of manual-based cognitive behavior therapy.

Main Outcome and Measure  Remission, defined as a 17-item Hamilton Depression Rating Scale score of 7 or less at both weeks 10 and 12, as assessed by raters blinded to treatment.

Results  Positive and negative predictors of remission were identified with a 2-way analysis of variance treatment (escitalopram or cognitive behavior therapy) × outcome (remission or nonresponse) interaction. Of 65 protocol completers, 38 patients with clear outcomes and usable positron emission tomography scans were included in the primary analysis: 12 remitters to cognitive behavior therapy, 11 remitters to escitalopram, 9 nonresponders to cognitive behavior therapy, and 6 nonresponders to escitalopram. Six limbic and cortical regions were identified, with the right anterior insula showing the most robust discriminant properties across groups (effect size = 1.43). Insula hypometabolism (relative to whole-brain mean) was associated with remission to cognitive behavior therapy and poor response to escitalopram, while insula hypermetabolism was associated with remission to escitalopram and poor response to cognitive behavior therapy.

Conclusions and Relevance  If verified with prospective testing, the insula metabolism-based treatment-specific biomarker defined in this study provides the first objective marker, to our knowledge, to guide initial treatment selection for depression.

Trial Registration  Registered at clinicaltrials.gov (NCT00367341)

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Figure 1.
Study Design and Outcomes

Outcome groups defined by Hamilton Depression Rating Scale (HDRS) scores. Remission was defined as an HDRS score of 7 or less; partial response, as an HDRS score decrease of more than 30% but not achieving remission; and nonresponse, as an HDRS score decrease of 30% or less. Escitalopram was given as escitalopram oxalate. CBT indicates cognitive behavior therapy and PET, positron emission tomography.

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Figure 2.
Potential Treatment-Specific Biomarker Candidates

Mean regional activity values for remitters and nonresponders segregated by treatment arm are plotted for the 6 regions showing a significant treatment × outcome analysis of variance interaction effect. Regional metabolic activity values are displayed as region/whole-brain metabolism converted to z scores. Regions match those shown in Table 2. Escitalopram was given as escitalopram oxalate. CBT indicates cognitive behavior therapy.

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Figure 3.
Right Anterior Insula as the Optimal Treatment-Specific Biomarker Candidate

Expanded view of findings. A, Scatterplot of insular activity from individual subjects in the remitter (REM) and nonresponder (NR) groups. Note: the anterior insula is the only region where the interaction subdivides patients into hypermetabolic (region/whole-brain mean >1.0) and hypometabolic (region/whole-brain mean <1.0) subgroups. B, Correlations of insula activity with percentage of change in Hamilton Depression Rating Scale (HDRS) score in the full cohort of subjects treated with cognitive behavior therapy (CBT) and escitalopram oxalate.

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Significance of right anterior insula activation for mental health intervention
Posted on June 26, 2013
Tegeler CH (1), Gerdes L (2), Lee SW (2), Shaltout H (1).
(1) Wake Forest School of Medicine, Winston-Salem, North Carolina. (2) Brain State Technologies LLC, Scottsdale, Arizona.
Conflict of Interest: Dr. Tegeler reports non-salary research funding from Brain State Technologies LLC in 2011, for a pilot clinical trial. Lee Gerdes and Dr. Lee are employees and shareholders of Brain State Technologies LLC. Dr. Shaltout reports no conflicts of interest.
We applaud McGrath and colleagues (2013) for exploring the use of brain state as a way to predict differential outcomes from either psychotherapy or medication as treatment for depression. Hypometabolism in the right anterior insula correlated with symptom reduction through cognitive behavioral therapy, whereas hypermetabolism in the right anterior insula correlated with symptom reduction through escitalopram. In their discussion the authors pointed out roles of the anterior insula for interoception, self-awareness, and cognitive control. We wish to highlight additionally that the insulae are loci for lateralized management of autonomic functioning. In particular the right anterior insula regulates sympathetic activity, and the left insula appears to be responsible for parasympathetic activation (Craig 2005; Cechetto et al., 2009; Beissner et al, 2013). Thus it may be that depressed individuals with greater right anterior insular activity have higher sympathetic arousal and are relatively impaired in their capacity to successfully apply cognitive-behavioral strategies. These individuals may preferentially benefit from anti-depressant medications, which can have effects on autonomic tone (Chang et al., 2012). In our own work we have found that hemispheric lateralization of autonomic management may be discerned through surface electroencephalic recordings, with clinical implications. We recently reported on a relationship between heart rate variability and high frequency temporal lobe electroencephalic asymmetry calculated from two-channel, one-minute recordings. Rightward temporal asymmetry correlated with higher heart rate and lower standard deviation of the RR interval (Tegeler et al. 2013). Furthermore in a clinical trial for individuals with insomnia and depressive symptoms we found a trend for auto-calibration of right dominant high frequency temporal activity towards greater symmetry to correlate with insomnia symptom reduction (Gerdes et al., 2013). We are thus excited that data from PET and surface electroencephalic recordings may be converging on a unitary conclusion about the role of lateralized activity in temporal lobe-region structures, for mental health intervention.Beissner F, Meissner K, Bar KJ, and Napadow V. (2013). The autonomic brain: an activation likelihood estimation meta-analysis for central processing of autonomic function. J Neurosci. 33(25): 10503-11.Cechetto DF and Shoemaker JK. (2009). Functional neuroanatomy of autonomic regulation. Neuroimage. 47(3): 795-803.Chang JS, Ha K, Yoon IY, Yoo CS, Yi SH, Her JY, Ha TH, and Park T. (2012). Patterns of cardiorespiratory coordination in young women with recurrent major depressive disorder treated with escitalopram or venlafaxine. Prog Neuropsychopharmacol Biol Psychiatry. 39(1): 136-42.Craig AD. (2005). Forebrain emotional asymmetry: a neuroanatomical basis? Trends Cogn Sci. 9(12): 566-71.Gerdes L, Gerdes P, Lee SW, and Tegeler C. (2013). HIRREM: a non-invasive, allostatic methodology for relaxation and auto-calibration of neural oscillations. Brain Behav. 3(2): 193-205.McGrath CL, Kelley ME, Holtzheimer PE, Dunlop BW, Craighead WE, Franco AR, Craddock RC, and Mayberg HS. (2013). Towards a neuroimaging treatment selection biomarker for major depressive disorder. JAMA Psychiatry. Jun 12: 1-9.Tegeler CH, Lee S, Tegeler C, and Shaltout H. (2013). Correlation between temporal lobe EEG asymmetry and heart rate variability. Neurology. Feb 12, 2013; 80 (Meeting abstracts 1): P03:031.
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