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Differences in Brain Glucose Metabolism Between Responders to CBT and Venlafaxine in a 16-Week Randomized Controlled Trial
Sidney H. Kennedy, M.D.; Jakub Z. Konarski, M.Sc.; Zindel V. Segal, Ph.D.; Mark A. Lau, Ph.D.; Peter J. Bieling, Ph.D.; Roger S. McIntyre, M.D.; Helen S. Mayberg, M.D.
Am J Psychiatry 2007;164:778-788. doi:10.1176/appi.ajp.164.5.778

Abstract

Objective: Neuroimaging investigations reveal changes in glucose metabolism (fluorine-18-fluorodeoxyglucose positron emission tomography [PET]) associated with response to disparate antidepressant treatment modalities, including cognitive behavior therapy (CBT), antidepressant pharmacotherapies, and deep brain stimulation. Using a nonrandomized design, the authors previously compared changes following CBT or paroxetine in depressed patients. In this study, the authors report changes in fluorine-18-fluorodeoxyglucose PET in responders to CBT or venlafaxine during a randomized controlled trial. MethodsSubjects meeting DSM-IV-TR criteria for a major depressive episode and a diagnosis of a major depressive disorder received a fluorine-18-fluorodeoxyglucose PET scan before randomization and after 16 weeks of antidepressant treatment with either CBT (N=12) or venlafaxine (N=12). Modality-specific and modality-independent regional brain metabolic changes associated with response status were analyzed. Results: Response rates were comparable between the CBT (7/12) and venlafaxine (9/12) groups. Response to either treatment modality was associated with decreased glucose metabolism bilaterally in the orbitofrontal cortex and left medial prefrontal cortex, along with increased metabolism in the right occipital-temporal cortex. Changes in metabolism in the anterior and posterior parts of the subgenual cingulate cortex and the caudate differentiated CBT and venlafaxine responders. Conclusions: Responders to either treatment modality demonstrated reduced metabolism in several prefrontal regions. Consistent with earlier reports, response to CBT was associated with a reciprocal modulation of cortical-limbic connectivity, while venlafaxine engaged additional cortical and striatal regions previously unreported in neuroimaging investigations.

Abstract Teaser
Figures in this Article

In general, evidence-based psychotherapies, specifically cognitive behavior therapy (CBT) and interpersonal psychotherapy, demonstrate comparable efficacy to pharmacotherapy in treating mild to moderate depression (1–3), although the evidence supporting the use of these psychotherapies in populations with severe depression is less established (4–6). Venlafaxine differs from selective serotonin reuptake inhibitor (SSRI) antidepressants by virtue of its ability to inhibit both serotonin and norepinephrine reuptake transporters (7, 8). Compared with SSRIs, venlafaxine has either comparable or superior rates of remission in the treatment of major depressive disorder (9–11).

Functional neuroimaging techniques, including fluorine-18-fluorodeoxyglucose positron emission tomography (PET) have helped to delineate regional differences in metabolic activity between depressed and nondepressed subjects (12, 13), as well as between depressed and remitted states (14–16). In the case of antidepressant medications, most investigators have focused on within-subject changes in cerebral metabolism before initiating and during treatment with various SSRIs or dual action antidepressants (15, 17–19, 20–22). Increased dorsolateral and decreased ventrolateral prefrontal metabolism have been reported most frequently in antidepressant respondents (15, 20–24).

There have been fewer investigations of changes in cerebral activity following psychological interventions (25–28). Limited evidence suggests predominantly right-sided decreases in prefrontal activity, with conflicting reports on anterior cingulate direction of change (25, 29). Nevertheless, these investigations provide support for the psychobiological impact of both psychotherapy and pharmacotherapy. Issues of nonrandomization and differences in response rates between medication and psychotherapy groups as well as differences in the duration of respective treatments have confounded previous reports (29).

In order to address these limitations, we carried out a randomized controlled trial to compare the patterns of change in cerebral metabolism in depressed patients following treatment for 16 weeks with CBT or venlafaxine. The specific aims of this study were twofold: 1) to delineate change patterns that distinguish responders to CBT from responders to venlafaxine and 2) to identify common regional metabolic changes associated with the response status with either treatment modality.

Based on our previous findings, we hypothesized that response to either treatment modality would be associated with changes in metabolism previously identified as differentiating the depressed and remitted states; response to CBT would be associated with additional prefrontal decreases reflecting the primacy of altered cognition (27, 29); and, in contrast, response to venlafaxine would be associated with subcortical activation, corresponding to neurovegetative symptom reduction (26, 30, 31).

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Participants

Thirty-one patients (13 men and 18 women) were recruited at the Centre for Addiction and Mental Health, a fully affiliated teaching hospital at the University of Toronto, Ontario, Canada. They were required to be between 20 and 50 years old; meet DSM-IV criteria for major depressive disorder; be currently in a major depressive episode as assessed by the Structured Clinical Interview for DSM-IV, Patient Edition (SCID-I/P) (32); and score 20 or greater on the 17-item Hamilton Depression Rating Scale (HAM-D) (33). They were also required to be free of any antidepressant medication for at least the preceding 2 weeks (4 weeks for fluoxetine) and be in good physical health with no evidence of neurological or other unstable medical conditions. Other axis I diagnoses, including concurrent anxiety disorders and substance abuse or dependence within the past 6 months, evidence of active suicidal ideation, pregnancy, and previous failure to respond to an adequate trial of CBT or venlafaxine were exclusion criteria. All subjects provided written informed consent for participation in this study, which was approved by the Research Ethics Board of Centre for Addiction and Mental Health.

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Treatment

Study participants were randomly assigned to receive either venlafaxine 75 mg/day to 225 mg/day (N=14) or CBT (N=17) for up to 16 weeks. Two subjects from the venlafaxine group and five subjects from the CBT group failed to complete a minimum of 8 weeks of treatment and a second PET scan (Figure 1). Subjects in the venlafaxine group received 75 mg daily for the first 2 weeks, thereafter increasing to a target dose range between 150 mg and 225 mg (Table 1).

Subjects in the CBT group received individualized outpatient sessions on a weekly basis, administered by a trained CBT therapist (Dr. Lau or Dr. Bieling, who have 12 and 10 years of experience, respectively, in delivering manual-based therapy according to the manual of Beck et al. [34]). All CBT sessions were audiotaped to enable ratings of treatment fidelity, which was confirmed by the supervising psychologist (Dr. Segal). Subjects undergoing CBT were taught to use a number of therapeutic strategies intended to reduce automatic reactivity to negative thoughts or attitudes and to combat dysphoric mood.

Therapists used a collaborative inquiry technique to guide subjects to a more evidence-based and less reactive reconstruction of their experience.

All subjects were evaluated biweekly using the HAM-D. Response was defined as a minimum reduction of 50% in HAM-D scores from baseline, and remission was defined as a HAM-D endpoint score <7.

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PET Procedure

PET measurements of regional cerebral glucose metabolism were obtained at baseline and again at the end of treatment, using standard imaging methods that have been previously described (29). Scans were acquired during the week before treatment initiation and within 1 week of the last treatment visit. For each scan, a 5 millicurie (mCi) (185 megabecquerels [Mbq]) fluorodeoxyglucose dose was injected intravenously, with image acquisition beginning after 40 minutes (PC 2048b; GEMS-Scanditronix, Uppsala, Sweden). All scans were acquired at a consistent time between 9 a.m. and noon, with subjects in a supine, awake, and resting state, with their eyes closed and ears uncovered. Subjects were asked to refrain from food, coffee, or alcohol intake for a minimum of 8 hours before each scan session.

Participants were given no explicit cognitive instructions but were asked to avoid ruminating on any one topic during the fluorodeoxyglucose uptake period. Wakefulness was additionally monitored every 10 minutes by a study investigator. Emission data were acquired during a 35-minute period (approximately 1 million counts per slice; 10 cm field of view). A customized, thermoplastic face mask was used to minimize head movement for the initial scan and for accurate repositioning at the second session. Raw images (15 parallel slices; 6.5 mm center-to-center interslice distance) were corrected for attenuation, reconstructed and smoothed to a final in-plane resolution of 7.0 mm at full width at half-maximum.

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Data Analysis

Statistical analyses were performed using statistical parametric mapping (SPM) (SPM99-Wellcome Department of Cognitive Neurology, London) implemented in Matlab (version 7.0; Mathworks Inc., Sherborn, Mass.) (35). The data were first screened for distributional properties, outliers, and missing values. All scans were normalized to the Montreal Neurological Institute International Consortium for Brain Mapping 152 stereotactic template within SPM99, which references brain locations in three-dimensional space relative to the anterior commissure. The images were then corrected for differences in the whole-brain global mean and smoothed using a Gaussian kernel to a final in-plane resolution of 12 mm at full width at half-maximum. Absolute glucose metabolic rates were not calculated.

Since response-specific CBT or venlafaxine effects were the primary foci of this study, results in this report are first presented for those participants (venlafaxine: N=9; CBT: N=7) who met the a priori-defined response criteria, and, subsequently, for those participants who did not meet a priori-defined response criteria (venlafaxine: N=3; CBT: N=5). To identify regional metabolic changes unique to each treatment modality, the contrast of prepost contrasts between CBT and venlafaxine treatments were evaluated to identify clusters meeting the p<0.01 height threshold for seven a priori-defined regions (orbitofrontal cortex [Brodmann’s areas 11, 47], dorsolateral prefrontal cortex [Brodmann’s area 9], anterior and posterior cingulate cortices, thalamus, striatum, and amygdala) and p<0.001 uncorrected for all other brain regions that also exceeded the minimum expected cluster size in SPM. Conjunction analyses (36) were also employed to identify the colocalization of significant baseline-endpoint changes that were common to both CBT- and venlafaxine-treated subjects, separately for responders and nonresponders.

The resulting t values were converted to z scores, with brain locations reported as x, y, and z coordinates in Montreal Neurological Institute space with approximate Brodmann’s areas identified by mathematical transformation of SPM99 coordinates into Talairach space.

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Clinical Effects

Twelve participants in each group completed at least 8 weeks of treatment and received both baseline and endpoint PET scans (Figure 1). In the CBT group, the mean HAM-D scores were 20.6 (SD=3.4) at baseline and 9.8 (SD=7.6) at endpoint, with a mean drop in severity of 53% (t=4.83, df=11, p=0.001). In the venlafaxine-treated group, the mean HAM-D scores were 20.3 (SD=3.0) at baseline and 7.4 (SD=4.9) at endpoint, representing a mean symptom reduction of 64% (t=8.13, df=11, p<0.001). There were no statistically significant between-group differences at either baseline (p=0.851) or endpoint (p=0.193). Nine of the 12 venlafaxine-treated subjects met criteria for response, and eight met criteria for remission. In the CBT group, seven of 12 subjects were classified as responders; of these, five met criteria for remission (Table 1). With the exception of one CBT responder, who received 12 weeks of treatment, all responders received 16 weeks of treatment.

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Neuroimaging Effects

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Responders

Before treatment initiation, there were no statistically significant between-group differences in brain glucose metabolism between subjects assigned to either CBT (N=12) or venlafaxine (N=12) (data not shown). Conjunction analysis identified the following changes common to both CBT and venlafaxine responders: decreased metabolism in the left and right lateral orbital frontal cortex (Brodmann’s areas 11, 47), the left dorsomedial prefrontal cortex (Brodmann’s area 8), along with increased metabolism in the right inferior occipital cortex (Figure 2, Table 2).

Response to treatment was also associated with differential changes in metabolism in several other regions. Whereas response to venlafaxine was associated with increases in the posterior cingulate (Brodmann’s area 29), CBT responders displayed decreased metabolism. Conversely, differential metabolic changes were also found in the left inferior temporal cortex (Brodmann’s areas 20, 21), increased with CBT and decreased with venlafaxine therapy (Figure 3). Additionally, metabolic changes unique to each treatment modality were observed. Decreased metabolism in the thalamus was found to be exclusive to CBT responders, while decreases in a region encompassing the right nucleus accumbens and a posterior part of the subgenual cingulate (Brodmann’s area 25) were only observed in venlafaxine responders. Responders to CBT displayed unique increases in metabolism in a region encompassing a more anterior portion of the subgenual cingulate/ventromedial frontal cortex (Brodmann’s area 32), as well as the right occipital-temporal cortex (Brodmann’s area 19), that were not observed in venlafaxine responders (Figure 4).

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Neuroimaging Effects

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Nonresponders

Left lateral orbitofrontal and left dorsolateral prefrontal decreases, along with decreases in the rostral anterior cingulate and globus pallidus, were common to both CBT and venlafaxine nonresponders (Figure 2, Table 2). Differential changes in metabolism were also observed between the CBT and venlafaxine nonresponder groups. Whereas nonresponse with venlafaxine treatment was associated with increases in the posterior thalamus and the dorsal insula, CBT nonresponders displayed decreased metabolism in these same brain regions (Figure 3).

Metabolic changes unique to each treatment modality were also noted within nonresponders. Decreases in the thalamus, putamen, dorsomedial and dorsolateral prefrontal cortices and the posterior thalamus were observed in the CBT group, while venlafaxine nonresponders were limited to increases in the ventral occipital cortex and dorsal cerebellum (Figure 4).

To our knowledge, this is the first report to evaluate changes in regional glucose metabolism following an extended 16-week randomized comparative trial of pharmacotherapy and CBT. These results extend our previous findings comparing CBT with paroxetine (29). In the present study, however, participants were randomly assigned to a treatment group, both groups received 16 weeks of treatment, a duration that reflects standard CBT practices, and response rates for the antidepressant and CBT were comparable.

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Common Regions

The colocalization of common regional brain metabolic changes associated with response to either CBT or venlafaxine represents treatment-independent effects of clinical response. Response to either treatment was associated with decreased metabolism in the ventrolateral and dorsomedial prefrontal cortices, changes that have previously differentiated depressed and euthymic states in major depressive disorder populations (16, 19, 25, 29). Differences in metabolic brain activity between baseline and endpoint in nonresponder groups included a combination of unique and similar metabolic brain changes (albeit of reduced magnitude) to those observed in responders. Preclinical data implicate the ventrolateral and orbitofrontal cortices in the modulation of behavioral and visceral responses to defensive, fearful, and reward-directed behaviors (37, 38). Through anatomical projections to neurons in the amygdala, striatum, hypothalamus, and other limbic and brainstem structures, the orbitofrontal cortex modulates responses to aversive or appetitive stimuli and integrates experiential stimuli with emotional salience (39, 40). Moreover, emotional processing biases in depressed patients have also been shown to map onto the orbitofrontal cortex (41, 42). In our analysis, response to either treatment was associated with a reduction in metabolic activity bilaterally in the orbitofrontal cortex, while decreased metabolism restricted to the left orbitofrontal cortex was observed irrespective of treatment group or treatment outcome.

The dorsomedial prefrontal cortex has been implicated in the self-referential processing of emotional stimuli. The right dorsomedial prefrontal cortex is activated in a wide range of emotional tasks, including recollection of affective-laden personal life events (43), attention to subjective feeling (44), and processing of emotion-related meanings (45). All of these tasks share an explicit representation of different aspects of the self and integration of these aspects with emotional reactions and experience (46). Decreases in dorsomedial prefrontal cortex activity, reported exclusively in the CBT group in our original study (29), were observed in both groups in this current investigation, perhaps reflecting the additional noradrenergic modulation by venlafaxine or the longer study duration. Nonresponse to either treatment was also associated with metabolic decreases in the dorsal prefrontal cortex, but in a region lateral and inferior (Brodmann’s area 9) to the locus identified in responders (Brodmann’s area 8). Moreover, nonresponse to either treatment was associated with decreased metabolism in the rostral anterior cingulate (Brodmann’s areas 24, 32) and left globus pallidus. Reduced activity in the rostral anterior cingulate has been previously reported as a predictor of treatment nonresponse (47–49).

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CBT Findings

Previously, we reported that response to CBT was associated with increased activity in the hippocampus and dorsal anterior cingulate (Brodmann’s area 24c) as well as decreases in the dorsolateral (Brodmann’s areas 9, 46), ventrolateral (Brodmann’s areas 47, 11), and medial (Brodmann’s areas 9, 10, 11) frontal cortices (29). In this new cohort, increases were localized to the anterior subgenual/ventromedial frontal cortex anterior cingulate (Brodmann’s area 32), while decreases were observed in comparable prefrontal regions (ventrolateral [Brodmann’s areas 47, 11] and dorsomedial [Brodmann’s area 8] frontal cortices). An accumulating evidentiary base supports disruptions in limbic–thalamic–cortical circuits, and limbic–cortical–striatal–pallidal–thalamic circuits as principal mediators of cognitive impairments in mood disorders (19, 48, 50). In contrast to our previous report, in this study we also observed decreases in the right thalamus accompanying CBT response, whereas metabolic decreases were localized to the left thalamus in CBT treatment nonresponders. Additional metabolic decreases in CBT nonresponders included bilateral reductions in the dorsolateral prefrontal cortex and the right putamen and globus pallidus. Analysis of the baseline-endpoint changes in subjects who did not respond to CBT may delineate metabolic patterns characterizing the effects of CBT administration, rather than antidepressant response to CBT treatment.

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Venlafaxine Findings

Decreases in glucose metabolism in the ventromedial frontal cortex (17, 20) and increases in the temporal cortex (18, 25) have been previously reported in SSRI responders. Venlafaxine-specific effects found in the subgenual cingulate (Brodmann’s area 25), ventrolateral prefrontal and temporal cortices, posterior cingulate (Brodmann’s area 29), and putamen replicate findings from studies of other antidepressant medications (22, 26, 29, 31).

Venlafaxine is a dual-action antidepressant that blocks the reuptake transport of both serotonin and norepinephrine and, as such, could be expected to demonstrate more extensive cortical engagement than previously observed single-action antidepressants. Serotonergic neurons in the dorsal raphe nucleus give rise to long axons that project throughout the brain (51), while the locus coeruleus in the pons is home to the majority of noradrenergic neurons with axonal projections to prefrontal cortical and subcortical sites, including the putamen, thalamus, and hippocampus (52). Variations in these regions across studies likely reflect study design differences in dose, treatment duration, and response variability (53). Our report of increased metabolism in the posterior thalamus, dorsal insula, and occipital cortex in subjects not responding to venlafaxine may reflect a specific SNRI-treatment effect.

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Psychotherapy-Pharmacotherapy Differences

In the previously reported post hoc comparison of brain changes associated with response to either CBT or paroxetine (29), there were the following baseline-endpoint changes within the cingulate cortex: increases in the dorsal anterior cingulate (Brodmann’s area 24c) with CBT treatment and decreases in the subgenual cingulate (Brodmann’s area 25) with response to paroxetine. These findings are replicated in the present study, with decreased right posterior subgenual cingulate activity in venlafaxine responders. Increased metabolism with CBT was localized to a different portion of the subgenual cingulate anterior, dorsal, and medial to the region identified with venlafaxine (Figure 4).

Decreased metabolism in the posterior subgenual cingulate has also been associated with response to SSRIs (19, 22, 25) and electroconvulsive therapy (54). Decreased subgenual cingulate activity with symptom abatement is consistent with other clinical neuroimaging data, reflecting a positive correlation between metabolic activity in the subgenual anterior cingulate and depression severity (55, 56). Taken together, this has provided the rationale for the subgenual cingulate (Brodmann’s area 25) as a target for deep brain stimulation in a treatment-resistant group of depressed patients (57).

Evidence from preclinical and human studies supports extensive reciprocal connections between the subgenual cingulate and areas implicated in the expression of behavioral, autonomic, and endocrine responses to stressors, aversive stimuli, and rewarding stimuli (40). Dysfunction of the ventral anterior cingulate cortex in primary mood disorders may thus contribute to the altered emotional behavior and neuroendocrine function evident in depression. Divergent subcortical findings of increased metabolism within the posterior cingulate in the venlafaxine group, compared with decreases accompanying response to CBT, may be associated with increased noradrenergic tone with venlafaxine treatment, leading to increased locus coeruleus-subcortical input (58). An analysis of treatment nonresponders further supports this hypothesis. Increases in the posterior thalamus and dorsal insula were reported in venlafaxine nonresponders, in contradistinction to the observed decreases associated with unsuccessful CBT treatment.

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Putative Mechanism Mediating Changes in Glucose Metabolism

A possible explanation for the observed changes in glucose metabolism at the cellular level is an alteration in glutamate signaling (59). Astrocytes, situated proximal to both cerebral capillary beds and neuronal synapses, play a pivotal role in the coupling of glucose uptake and glutamatergic neurotransmission (60). Following the release of glutamate by the presynaptic neuron, its activity on the postsynaptic surface is quickly terminated by glutamate reuptake into the surrounding glia (61). Subsequent glutamate reuptake by glia stimulates glucose uptake and metabolism by astrocytes, adenosine triphosphate-generating processes which ultimately lead to the recycling of glutamate back to glutamine (50). In keeping with this view, changes in neurotransmission, represented by glutamatergic synaptic activity, are believed to reflect differences in the fluorine-18-fluorodeoxyglucose-PET signal (62).

Intracellular glucose delivery is dependent on several isoforms of facilitative glucose transporters (63). Exposure to some dual-action antidepressants has been linked to increases in glucose transporter messenger ribonucleic acid (mRNA) levels (64), whereas exposure to some tricyclic antidepressants may actually inhibit glucose transport (65). Recently, greater scrutiny of the metabolic effects of psychotropic medications has highlighted the association between some noradrenergic antidepressants, hyperglycemia, and increased sensitivity to endogenous counterregulatory mediators (66).

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Limitations

There are several limitations to this investigation. Our relatively small cohort size may have precluded the identification of subthreshold changes in brain activity because of power constraints, particularly in our analysis of nonresponder changes. We did not acquire arterial radioactivity levels, preventing a calculation of absolute glucose metabolism. In the absence of high-resolution structural magnetic resonance images, region-of-interest analyses were not performed. While the homogeneity of this population represents a strength, it may also limit generalizability of our findings to real-world populations of depressed patients where medical and psychiatric comorbidities are frequently encountered.

Another limitation is the acquisition of resting-state scans, rather than obtaining brain responses to affective or cognitive challenges before and following treatment. Recent data suggest that this latter approach can reveal residual relapse vulnerability following successful pharmacological or cognitive intervention (67). Since we did not acquire neuroimaging data early in the course of treatment (e.g., after 1 week), we were unable to examine the potential predictive value of early change on subsequent clinical outcome. Finally, we did not include self-rated psychometric evaluations to complement symptom measurement with the HAM-D.

Clinical experience suggests that some patients respond better to psychotherapy and others to pharmacotherapy. This study helps to build an emerging evidence base for differential changes in regional brain activity following response (and nonresponse) to pharmacotherapy compared with psychotherapy (13, 21, 25, 28, 29). Exploration of baseline differences between venlafaxine and CBT responders may also help to understand which patients are best served by each of the therapeutic interventions that were evaluated.

+Presented at the Society of Biological Psychiatry, Poster #736, Toronto, May 18-20, 2006; American Psychiatry Association, Poster #937, Toronto, May 20-25, 2006. Received June 13, 2006; revisions received Aug. 28, Sept. 29, and Nov. 21, 2006; accepted Dec. 7, 2006. From the University Health Network, Toronto; Institute of Medical Science, University of Toronto, Toronto; Departments of Psychiatry and Psychology, University of Toronto, Toronto; Centre for Addiction and Mental Health, Toronto; St. Joseph’s Healthcare, Hamilton, Ontario, Canada; Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada; Department of Psychiatry and Neurology, Emory University, Atlanta; and the Rotman Research Institute, Baycrest Centre, Ontario, Canada. Address correspondence and reprint requests to Dr. Kennedy, University Health Network, Toronto General Hospital, 200 Elizabeth St., Eaton North Wing 8-222, Toronto, Ontario M5G 2C4, Canada; sidney.kennedy@uhn.on.ca (e-mail).

+Supported by the Canadian Institutes of Health Research and Wyeth Pharmaceuticals.

+The authors thank the research assistant teams and the PET centre staff for their assistance in the trial.

+CME Disclosure: Dr. Kennedy has received honoraria from Biovail, Eli Lilly, GlaxoSmithKline, Janssen-Ortho, Lundbeck, Organon, Servier, and Wyeth Pharmaceuticals; he has received consultant fees from Advanced Neuromodulation Systems, Inc., Biovail, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen-Ortho, Lundbeck, Organon, Pfizer, Servier, and Wyeth; he has also received grant funding from AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen-Ortho, Lundbeck, and Merck Frosst. Mr. Konarski has received grant funding from Eli Lilly; consultant fees from AstraZeneca, Janssen-Ortho, and Wyeth Pharmaceuticals; and travel honoraria from GlaxoSmithKline. Dr. Bieling has received speaker"s honorarium from Wyeth Pharmaceuticals. Dr. McIntyre is a consultant for Bristol-Myers Squibb and a consultant and speaker for AstraZeneca, Eli Lilly, Janssen-Ortho, Organon, Wyeth Pharmaceuticals, Lundbeck, GlaxoSmithKline, Oryx, Biovail, Pfizer, and Prestwick; he has also received research funding from Wyeth Pharmaceuticals, GlaxoSmithKline, Merck, Servier, and AstraZeneca. Dr. Mayberg is a consultant for Cyberonics and Advanced Neuromodulation Systems, Inc.; she has an intellectual/property licensing agreement with Advanced Neuromodulation Systems, Inc., and has received research symposium and travel honoraria from AstraZeneca. Drs. Segal and Lau report no competing interests. APA policy requires disclosure by CME authors of unapproved or investigational use of products discussed in CME programs. Off-label use of medications by individual physicians is permitted and common. Decisions about off-label use can be guided by scientific literature and clinical experience.

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27.Roffman JL, Marci CD, Glick DM, Dougherty DD, Rauch SL: Neuroimaging and the functional neuroanatomy of psychotherapy. Psychol Med 2005; 35:1385–1398
 
28.Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple K, Kennedy S, Segal Z, Rafi-Tari S: Limbic-frontal circuitry in major depression: a path modeling metanalysis. Neuroimage 2004; 22:409–418
 
29.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
 
30.Davidson RJ, Irwin W, Anderle MJ, Kalin NH: The neural substrates of affective processing in depressed patients treated with venlafaxine. Am J Psychiatry 2003; 160:64–75
 
31.Davies J, Lloyd KR, Jones IK, Barnes A, Pilowsky LS: Changes in regional cerebral blood flow with venlafaxine in the treatment of major depression. Am J Psychiatry 2003; 160:374–376
 
32.First MB, Spitzer RL, Gibbon M, Williams JBW: Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition (SCID/P), Version 2. New York, New York State Psychiatric Institute, Biometrics Research 1995
 
33.Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56–62
 
34.Beck AT, Rush AJ, Shaw B, Emery G: Cognitive Therapy of Depression. New York, Guilford, 1979
 
35.Friston K, Holmes A, Worsley K, Poline J, Frith C, Frackowiak R: Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 1995; 2:189–210
 
36.Price CJ, Friston KJ: Cognitive conjunction: a new approach to brain activation experiments. Neuroimage 1997; 5(Pt 1):261–270
 
37.Rolls ET: The orbitofrontal cortex and reward. Cereb Cortex 2000; 10:284–294
 
38.Rolls ET: The functions of the orbitofrontal cortex. Brain Cogn 2004; 55:11–29
 
39.Carmichael ST, Price JL: Limbic connections of the orbital and medial prefrontal cortex in macaque monkeys. J Comp Neurol 1995; 363:615–641
 
40.Ongur D, Price JL: The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex 2000; 10:206–219
 
41.Elliott R, Rubinsztein JS, Sahakian BJ, Dolan RJ: The neural basis of mood-congruent processing biases in depression. Arch Gen Psychiatry 2002; 59:597–604
 
42.Phillips ML, Drevets WC, Rauch SL, Lane R: Neurobiology of emotion perception, II: implications for major psychiatric disorders. Biol Psychiatry 2003; 54:515–528
 
43.Reiman EM, Lane RD, Ahern GL, Schwartz GE, Davidson RJ, Friston KJ, Yun LS, Chen K: Neuroanatomical correlates of externally and internally generated human emotion. Am J Psychiatry 1997; 154:918–925
 
44.Lane RD, Reiman EM, Ahern GL, Schwartz GE, Davidson RJ: Neuroanatomical correlates of happiness, sadness, and disgust. Am J Psychiatry 1997; 154:926–933
 
45.Teasdale JD, Howard RJ, Cox SG, Ha Y, Brammer MJ, Williams SC, Checkley SA: Functional MRI study of the cognitive generation of affect. Am J Psychiatry 1999; 156:209–215
 
46.Fossati P, Hevenor SJ, Graham SJ, Grady C, Keightley ML, Craik F, Mayberg H: In search of the emotional self: an fmri study using positive and negative emotional words. Am J Psychiatry 2003; 160:1938–1945
 
47.Mayberg HS: Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci 1997; 9:471–481
 
48.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
 
49.Saxena S, Brody AL, Ho ML, Zohrabi N, Maidment KM, Baxter LR Jr: Differential brain metabolic predictors of response to paroxetine in obsessive-compulsive disorder versus major depression. Am J Psychiatry 2003; 160:522–532
 
50.Takahashi S, Driscoll BF, Law MJ, Sokoloff L: Role of sodium and potassium ions in regulation of glucose metabolism in cultured astroglia. Proc Natl Acad Sci U S A 1995; 92:4616–4620
 
51.Delgado PL: Depression: the case for a monoamine deficiency. J Clin Psychiatry 2000; 61(suppl6):7–11
 
52.Delgado PL, Moreno FA: Role of norepinephrine in depression. J Clin Psychiatry 2000; 61(suppl1):5–12
 
53.Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, Silva JA, Tekell JL, Martin CC, Lancaster JL, Fox PT: Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry 1999; 156:675–682
 
54.Nobler MS, Oquendo MA, Kegeles LS, Malone KM, Campbell CC, Sackeim HA, Mann JJ: Decreased regional brain metabolism after ect. Am J Psychiatry 2001; 158:305–308
 
55.Drevets WC: Prefrontal cortical-amygdalar metabolism in major depression. Ann N Y Acad Sci 1999; 877:614–637
 
56.Osuch EA, Ketter TA, Kimbrell TA, George MS, Benson BE, Willis MW, Herscovitch P, Post RM: Regional cerebral metabolism associated with anxiety symptoms in affective disorder patients. Biol Psychiatry 2000; 48:1020–1023
 
57.Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH: Deep brain stimulation for treatment-resistant depression. Neuron 2005; 45:651–660
 
58.Hurlemann R, Hawellek B, Matusch A, Kolsch H, Wollersen H, Madea B, Vogeley K, Maier W, Dolan RJ: Noradrenergic modulation of emotion-induced forgetting and remembering. J Neurosci 2005; 25:6343–6349
 
59.Magistretti PJ, Pellerin L: Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. Philos Trans R Soc Lond B Biol Sci 1999; 354:1155–1163
 
60.Petroff OA: GABA and glutamate in the human brain Neuroscientist 2002; 8:562–573
 
61.Danbolt NC: The high affinity uptake system for excitatory amino acids in the brain. Prog Neurobiol 1994; 44:377–396
 
62.Magistretti PJ, Pellerin L: Functional brain imaging: role metabolic coupling between astrocytes and neurons. Rev Med Suisse Romande 2000; 120:739–742
 
63.Duelli R, Kuschinsky W: Brain glucose transporters: relationship to local energy demand. News Physiol Sci 2001; 1671–1676
 
64.Heiser P, Singh S, Krieg JC, Vedder H: Effects of different antipsychotics and the antidepressant mirtazapine on glucose transporter MRNA levels in human blood cells. J Psychiatr Res 2006; 40:374–379
 
65.Pinkofsky HB, Dwyer DS, Bradley RJ: The inhibition of glut1 glucose transport and cytochalasin B binding activity by tricyclic antidepressants. Life Sci 2000; 66:271–278
 
66.McIntyre RS, Soczynska JK, Konarski JZ, Kennedy SH: The effect of antidepressants on glucose homeostasis and insulin sensitivity: synthesis and mechanisms. Expert Opin Drug Saf 2006; 5:157–168
 
67.Segal ZV, Kennedy SH, Gemar M, Hood K, Pedersen R, and Buis T. Cognitive reactivity to sad mood provocation and the prediction of depressive relapse. Arch Gen Psychiatry 2006; 63:749–755
 
 
Figure 1. Randomized Controlled Trial Subject Enrollment Flowchart
 
Figure 2. Changes in Regional Glucose Metabolism Common to CBT Responders and Venlafaxine Responders (left), CBT and Venlafaxine Nonresponders (right)—Same Region, Same Directiona

aLeft: Changes in regional glucose metabolism (fluorine-18-fluorodeoxyglucose PET) common to CBT responders and venlafaxine responders following treatment. Lateral orbitofrontal and dorsomedial prefrontal decreases, along with increases in the inferior occipital cortex, were seen with response to either treatment modality. Right: Changes in regional glucose metabolism (fluorine-18-fluorodeoxyglucose PET) common to CBT nonresponders and venlafaxine nonresponders following treatment. Left lateral orbitofrontal and left dorsolateral prefrontal decreases, along with decreases in the rostral anterior cingulate and globus pallidus, were observed with exposure to either treatment modality.

 
Figure 3. Changes in Regional Glucose Metabolism Following Treatment in Responders (left), Nonresponders (right)—Same Region, Opposite Direction a

aLeft: Changes in regional glucose metabolism (fluorine-18-fluorodeoxyglucose PET) following treatment in responders. Regions with metabolic increases in CBT responders and decreases in venlafaxine responders are shown, as well as regions with metabolic decreases in CBT responders and increases in venlafaxine responders. Right: Changes in regional glucose metabolism (fluorine-18-fluorodeoxyglucose PET) following treatment in nonresponders. Regions with metabolic decreases in CBT nonresponders and increases in venlafaxine nonresponders are shown.

 
Figure 4. Changes in Regional Glucose Metabolism Following Successful and Unsuccessful Treatment—Unique Regionsa

aLeft: Changes in regional glucose metabolism (fluorine-18-fluorodeoxyglucose PET) following treatment. Regions with metabolic changes unique to CBT responders included decreases (blue) in the thalamus and increases (red) in the anterior subgenual cingulate. Regions with metabolic changes unique to venlafaxine responders were limited to decreases (blue) in the posterior subgenual cingulate. Right: Changes in regional glucose metabolism (fluorine-18-fluorodeoxyglucose PET) following unsuccessful treatment. Regions with metabolic changes unique to unsuccessful CBT included decreases (blue) in the putamen, dorsomedial and dorsolateral prefrontal cortex and the posterior thalamus. Regions with metabolic changes unique to venlafaxine nonresponders were limited to increases in the ventral occipital cortex and dorsal cerebellum.

Figure 1. Randomized Controlled Trial Subject Enrollment Flowchart

Figure 2. Changes in Regional Glucose Metabolism Common to CBT Responders and Venlafaxine Responders (left), CBT and Venlafaxine Nonresponders (right)—Same Region, Same Directiona

aLeft: Changes in regional glucose metabolism (fluorine-18-fluorodeoxyglucose PET) common to CBT responders and venlafaxine responders following treatment. Lateral orbitofrontal and dorsomedial prefrontal decreases, along with increases in the inferior occipital cortex, were seen with response to either treatment modality. Right: Changes in regional glucose metabolism (fluorine-18-fluorodeoxyglucose PET) common to CBT nonresponders and venlafaxine nonresponders following treatment. Left lateral orbitofrontal and left dorsolateral prefrontal decreases, along with decreases in the rostral anterior cingulate and globus pallidus, were observed with exposure to either treatment modality.

Figure 3. Changes in Regional Glucose Metabolism Following Treatment in Responders (left), Nonresponders (right)—Same Region, Opposite Direction a

aLeft: Changes in regional glucose metabolism (fluorine-18-fluorodeoxyglucose PET) following treatment in responders. Regions with metabolic increases in CBT responders and decreases in venlafaxine responders are shown, as well as regions with metabolic decreases in CBT responders and increases in venlafaxine responders. Right: Changes in regional glucose metabolism (fluorine-18-fluorodeoxyglucose PET) following treatment in nonresponders. Regions with metabolic decreases in CBT nonresponders and increases in venlafaxine nonresponders are shown.

Figure 4. Changes in Regional Glucose Metabolism Following Successful and Unsuccessful Treatment—Unique Regionsa

aLeft: Changes in regional glucose metabolism (fluorine-18-fluorodeoxyglucose PET) following treatment. Regions with metabolic changes unique to CBT responders included decreases (blue) in the thalamus and increases (red) in the anterior subgenual cingulate. Regions with metabolic changes unique to venlafaxine responders were limited to decreases (blue) in the posterior subgenual cingulate. Right: Changes in regional glucose metabolism (fluorine-18-fluorodeoxyglucose PET) following unsuccessful treatment. Regions with metabolic changes unique to unsuccessful CBT included decreases (blue) in the putamen, dorsomedial and dorsolateral prefrontal cortex and the posterior thalamus. Regions with metabolic changes unique to venlafaxine nonresponders were limited to increases in the ventral occipital cortex and dorsal cerebellum.

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17.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
 
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25.Brody AL, Saxena S, Stoessel P, Gillies LA, Fairbanks LA, Alborzian S, Phelps ME, Huang SC, Wu HM, Ho ML, Ho MK, Au SC, Maidment K, Baxter LR Jr: Regional brain metabolic changes in patients with major depression treated with either paroxetine or interpersonal therapy: preliminary findings. Arch Gen Psychiatry 2001; 58:631–640
 
26.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
 
27.Roffman JL, Marci CD, Glick DM, Dougherty DD, Rauch SL: Neuroimaging and the functional neuroanatomy of psychotherapy. Psychol Med 2005; 35:1385–1398
 
28.Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple K, Kennedy S, Segal Z, Rafi-Tari S: Limbic-frontal circuitry in major depression: a path modeling metanalysis. Neuroimage 2004; 22:409–418
 
29.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
 
30.Davidson RJ, Irwin W, Anderle MJ, Kalin NH: The neural substrates of affective processing in depressed patients treated with venlafaxine. Am J Psychiatry 2003; 160:64–75
 
31.Davies J, Lloyd KR, Jones IK, Barnes A, Pilowsky LS: Changes in regional cerebral blood flow with venlafaxine in the treatment of major depression. Am J Psychiatry 2003; 160:374–376
 
32.First MB, Spitzer RL, Gibbon M, Williams JBW: Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition (SCID/P), Version 2. New York, New York State Psychiatric Institute, Biometrics Research 1995
 
33.Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56–62
 
34.Beck AT, Rush AJ, Shaw B, Emery G: Cognitive Therapy of Depression. New York, Guilford, 1979
 
35.Friston K, Holmes A, Worsley K, Poline J, Frith C, Frackowiak R: Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 1995; 2:189–210
 
36.Price CJ, Friston KJ: Cognitive conjunction: a new approach to brain activation experiments. Neuroimage 1997; 5(Pt 1):261–270
 
37.Rolls ET: The orbitofrontal cortex and reward. Cereb Cortex 2000; 10:284–294
 
38.Rolls ET: The functions of the orbitofrontal cortex. Brain Cogn 2004; 55:11–29
 
39.Carmichael ST, Price JL: Limbic connections of the orbital and medial prefrontal cortex in macaque monkeys. J Comp Neurol 1995; 363:615–641
 
40.Ongur D, Price JL: The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex 2000; 10:206–219
 
41.Elliott R, Rubinsztein JS, Sahakian BJ, Dolan RJ: The neural basis of mood-congruent processing biases in depression. Arch Gen Psychiatry 2002; 59:597–604
 
42.Phillips ML, Drevets WC, Rauch SL, Lane R: Neurobiology of emotion perception, II: implications for major psychiatric disorders. Biol Psychiatry 2003; 54:515–528
 
43.Reiman EM, Lane RD, Ahern GL, Schwartz GE, Davidson RJ, Friston KJ, Yun LS, Chen K: Neuroanatomical correlates of externally and internally generated human emotion. Am J Psychiatry 1997; 154:918–925
 
44.Lane RD, Reiman EM, Ahern GL, Schwartz GE, Davidson RJ: Neuroanatomical correlates of happiness, sadness, and disgust. Am J Psychiatry 1997; 154:926–933
 
45.Teasdale JD, Howard RJ, Cox SG, Ha Y, Brammer MJ, Williams SC, Checkley SA: Functional MRI study of the cognitive generation of affect. Am J Psychiatry 1999; 156:209–215
 
46.Fossati P, Hevenor SJ, Graham SJ, Grady C, Keightley ML, Craik F, Mayberg H: In search of the emotional self: an fmri study using positive and negative emotional words. Am J Psychiatry 2003; 160:1938–1945
 
47.Mayberg HS: Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci 1997; 9:471–481
 
48.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
 
49.Saxena S, Brody AL, Ho ML, Zohrabi N, Maidment KM, Baxter LR Jr: Differential brain metabolic predictors of response to paroxetine in obsessive-compulsive disorder versus major depression. Am J Psychiatry 2003; 160:522–532
 
50.Takahashi S, Driscoll BF, Law MJ, Sokoloff L: Role of sodium and potassium ions in regulation of glucose metabolism in cultured astroglia. Proc Natl Acad Sci U S A 1995; 92:4616–4620
 
51.Delgado PL: Depression: the case for a monoamine deficiency. J Clin Psychiatry 2000; 61(suppl6):7–11
 
52.Delgado PL, Moreno FA: Role of norepinephrine in depression. J Clin Psychiatry 2000; 61(suppl1):5–12
 
53.Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, Silva JA, Tekell JL, Martin CC, Lancaster JL, Fox PT: Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry 1999; 156:675–682
 
54.Nobler MS, Oquendo MA, Kegeles LS, Malone KM, Campbell CC, Sackeim HA, Mann JJ: Decreased regional brain metabolism after ect. Am J Psychiatry 2001; 158:305–308
 
55.Drevets WC: Prefrontal cortical-amygdalar metabolism in major depression. Ann N Y Acad Sci 1999; 877:614–637
 
56.Osuch EA, Ketter TA, Kimbrell TA, George MS, Benson BE, Willis MW, Herscovitch P, Post RM: Regional cerebral metabolism associated with anxiety symptoms in affective disorder patients. Biol Psychiatry 2000; 48:1020–1023
 
57.Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH: Deep brain stimulation for treatment-resistant depression. Neuron 2005; 45:651–660
 
58.Hurlemann R, Hawellek B, Matusch A, Kolsch H, Wollersen H, Madea B, Vogeley K, Maier W, Dolan RJ: Noradrenergic modulation of emotion-induced forgetting and remembering. J Neurosci 2005; 25:6343–6349
 
59.Magistretti PJ, Pellerin L: Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. Philos Trans R Soc Lond B Biol Sci 1999; 354:1155–1163
 
60.Petroff OA: GABA and glutamate in the human brain Neuroscientist 2002; 8:562–573
 
61.Danbolt NC: The high affinity uptake system for excitatory amino acids in the brain. Prog Neurobiol 1994; 44:377–396
 
62.Magistretti PJ, Pellerin L: Functional brain imaging: role metabolic coupling between astrocytes and neurons. Rev Med Suisse Romande 2000; 120:739–742
 
63.Duelli R, Kuschinsky W: Brain glucose transporters: relationship to local energy demand. News Physiol Sci 2001; 1671–1676
 
64.Heiser P, Singh S, Krieg JC, Vedder H: Effects of different antipsychotics and the antidepressant mirtazapine on glucose transporter MRNA levels in human blood cells. J Psychiatr Res 2006; 40:374–379
 
65.Pinkofsky HB, Dwyer DS, Bradley RJ: The inhibition of glut1 glucose transport and cytochalasin B binding activity by tricyclic antidepressants. Life Sci 2000; 66:271–278
 
66.McIntyre RS, Soczynska JK, Konarski JZ, Kennedy SH: The effect of antidepressants on glucose homeostasis and insulin sensitivity: synthesis and mechanisms. Expert Opin Drug Saf 2006; 5:157–168
 
67.Segal ZV, Kennedy SH, Gemar M, Hood K, Pedersen R, and Buis T. Cognitive reactivity to sad mood provocation and the prediction of depressive relapse. Arch Gen Psychiatry 2006; 63:749–755
 
+
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