Toward a neuroimaging treatment selection biomarker for major depressive disorder

Abstract

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).

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.

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.

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.