Decreased occipital cortical glutamate levels in response to successful cognitive-behavioral therapy and pharmacotherapy for major depressive disorder

Abstract

Background: Previous studies have demonstrated that antidepressant medication and electroconvulsive therapy increase occipital cortical γ-aminobutyric acid (GABA) in major depressive disorder (MDD), but a small pilot study failed to show a similar effect of cognitive-behavioral therapy (CBT) on occipital GABA. In light of these findings we sought to determine if baseline GABA levels predict treatment response and to broaden the analysis to other metabolites and neurotransmitters in this larger study.

Methods: A total of 40 MDD outpatients received baseline proton magnetic resonance spectroscopy (1H-MRS), and 30 subjects completed both pre- and post-CBT 1H-MRS; 9 CBT nonresponders completed an open-label medication phase followed by an additional/3rd 1H-MRS. The magnitude of treatment response was correlated with occipital amino acid neurotransmitter levels.

Results: Baseline GABA did not predict treatment outcome. Furthermore, there was no significant effect of CBT on GABA levels. However, we found a significant group × time interaction (F1, 28 = 6.30, p = 0.02), demonstrating reduced glutamate in CBT responders, with no significant glutamate change in CBT nonresponders.

Conclusions: These findings corroborate the lack of effect of successful CBT on occipital cortical GABA levels in a larger sample. A reduction in glutamate levels following treatment, on the other hand, correlated with successful CBT and antidepressant medication response. Based on this finding and other reports, decreased occipital glutamate may be an antidepressant response biomarker. Healthy control comparator and nonintervention groups may shed light on the sensitivity and specificity of these results.

Figure 1. Study Design and Subject Flow

A. Study Design – Unipolar unmedicated depressed subjects in a current major depressive episode meeting inclusion/exclusion criteria (Phase I) received a baseline ¹H-MRS before starting 12 weeks of once-weekly structured CBT with clinician-administered psychiatric ratings every four weeks (Phase IIa). A second ¹H-MRS was performed for all subjects retained at the end of Phase IIa (or after at least eight weeks if the subject dropped-out). CBT non-responders were then offered a 6-week course of an SSRI (Phase IIb). All subjects retained at the end of Phase Ib received a third and final ¹H-MRS at study exit. B. Subject Flow – All available data were used in the analysis. Last Observation Carried Forward (LOCF) was used for patients with one post-treatment follow-up visit (at least 4 weeks of CBT). ^aA total of 8 subjects did not have a baseline ¹H-MRS for the following reasons: contraindication to MRI (N=4), poor quality spectra (N=2), excessive motion artifact (N=1), poor water suppression (N=1). ^bMR contraindication (N=4), poor quality spectra (N=2), exited the study (N=11; 5 started medications, 1 poor adherence to study procedures, 1 no time for appointments, 1 had knee surgery, 1 moved to a different city, and 2 were lost to follow-up). ^cSubjects who completed at least 8 weeks of CBT received the second MRS. Eight subjects exited the study before completing 4 weeks of CBT (4 started medications, 1 moved to a different city, 1 had knee surgery, and 2 were lost to follow-up before receiving any CBT), 3 exited before 8 weeks of CBT (1 started medications, 1 no time for appointments, and 1 poor adherence to study procedures), and 5 exited before 12 weeks of CBT (2 started medications, 1 moved to another city, 1 got a new job, and 1 was lost to follow-up). Abbreviations: N: number of subjects; ¹H-MRS: proton magnetic resonance spectroscopy; CBT: cognitive-behavioral therapy.

Figure 2. Successful CBT for MDD Is Associated With Decreased Glutamate Levels in the Occipital Cortex

Unipolar unmedicated depressed subjects in a current major depressive episode received 12 weeks of once-weekly structured CBT with 30 completing both pre- and post-CBT MRS. A. Treatment responders (≥ 50% reduction in HDRS₂₄) showed a significant reduction in occipital glutamate levels [group-by-time interaction (F_(1,28) = 6.30, p = 0.02)]. B & C. Similarly, reductions in the secondary depression and anxiety outcome measures, BDI (r_s = 0.46, p = 0.01) and HAM-A (r_s = 0.48, p = 0.01), were positively correlated with decreased occipital glutamate.

Figure 3. In CBT Non-Responders, Positive SSRI Response Is Associated With Decreased Glutamate in the Occipital Cortex

Unipolar unmedicated depressed subjects in a current major depressive episode received 12 weeks of once-weekly structured CBT. Of the 14 subjects who entered phase 2 due to CBT non-response, nine completed all neuroimaging and clinical assessments. In the medicated CBT non-responders, reductions in BDI and HDRS were positively correlated with reductions in occipital cortical glutamate.