Various lines of research suggest that neurotrophic processes in the hippocampus are key mechanisms in major depressive disorder and are of relevance for response to antidepressive treatment. We performed proton magnetic resonance spectroscopy (1H-MRS) of the hippocampus at 3 T in 18 unmedicated subjects with unipolar major depressive episodes and in 10 age- and gender-matched healthy volunteers. Thirteen patients underwent a second examination after 8 wk treatment with either citalopram (n=7) or nortriptyline (n=6). Of these patients, 11 MRS datasets could be used for the assessment of treatment correlates. In the cross-sectional comparison, we observed a significant reduction of the metabolic ratios Glx/Cr (Glx=glutamine, glutamate and gamma-aminobutyric acid) and glutamine (Gln)/Cr in the patient group. The Gln/Glx ratio also showed a trend towards significant reduction. The individual effect of treatment correlated with an increase in the absolute concentrations of N-acetylaspartate (NAA) and of choline compounds (Cho). Low baseline NAA and Cho levels predicted positive treatment effects. There was no difference in any clinical or metabolic measure, either at baseline or at follow-up between the two treatment groups (citalopram, nortriptyline). Our data provide first evidence for a reduction of Gln in the hippocampus of subjects with major depression. Furthermore, we provide first evidence in patients with major depression for neurorestorative effects in the hippocampus by pharmacological treatment expressed by a correlation of NAA and Cho increases with treatment response. This accounts in particular for those patients with low NAA and Cho baseline levels.