<b><i>Background:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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 (F_{1, 28} = 6.30, p = 0.02), demonstrating reduced glutamate in CBT responders, with no significant glutamate change in CBT nonresponders. <b><i>Conclusions:</i></b> 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.