Discussion
non-psychotic depression, psychotic depression, treatment-resistant depression, psychosis, MDD, depression
REMISSION, MRS
To our knowledge, this is the first MRS study to examine metabolite levels in vivo in patients with psychotic depression. Cross-sectionally, in remitted patients with psychotic depression compared to non-psychiatric controls, we observed higher myo-inositol levels in the dACC. We did not find differences between groups in Glx, Cho, tNAA, and Cr. Longitudinally, patients randomized to placebo demonstrated a decrease in Cr levels in the dACC; the changes in metabolite levels were significantly greater compared to those who remained on olanzapine. We did not find differences between treatment groups in the changes in Glx, Cho, myo-inositol and tNAA. Based on our results, we speculate that olanzapine may sustain remission from psychotic depression by maintaining Cr levels in the dACC.Taken together, our findings may be explained by the glial cell disruption hypothesis in depression with respect to myo-inositol suppression. Myo-inositol is considered a glial cell marker since it is transported into astrocytes actively (Griffin et al., In human MRS studies in drug-free patients, low myo-inositol level is reported in the ACC in unmedicated patients with MDD (Shirayama et al., With respect to treatment-related metabolite change, previous studies have reported an increase in myo-inositol levels following treatment. Repetitive transcranial magnetic stimulation increased prefrontal myo-inositol in treatment-resistant depression, which was associated with clinical improvement (Zheng et al., In our study, we found higher myo-inositol levels in the dACC in remitted patients with depression compared to controls. Our study focused on patients who attained remission after treatment with sertraline plus olanzapine. Higher myo-inositol levels may reflect the consequence of this treatment, given that previous studies reported reduced myo-inositol levels in non-psychotic depression and not altered in psychosis, and increases in myo-inositol levels after antidepressant treatments. Future prospective studies are needed to elucidate the effects of antidepressants or placebo on the change in myo-inositol in relation to the treatment outcome, and to identify the role of myo-inositol in depression.Our longitudinal analysis suggests that olanzapine maintains Cr level in the dACC of patients with remitted psychotic depression. Creatine mainly plays a role in energy metabolism, osmoregulation, and neurotransmission (Rackayova et al., Another sensitivity analysis limited to patients who were assigned to placebo found that relapsed patients demonstrated a greater decrease in Cho, myo-inositol, and tNAA in the dACC compared to the sustained remission group. This is consistent with previous studies which reported that successful treatment increased choline and myo-inositol levels (Sonawalla et al., Findings from this study should be considered in light of some limitations. First, we were unable to combine the data from all four sites because the excluded two sites did not have water-scaled data and the acquisition parameters such as TE and CRLB of each metabolite were different across sites. Therefore, we harmonized the effect size of the two sites meta-analytically. Since the tissue fractions, FWHM, and SNR were different across the two sites in the L-DLPFC due to different voxel dimensions, and fGM in this voxel was relatively low, our L-DLPFC findings should be interpreted cautiously. Moreover, dACC voxel was placed bilaterally, which would reduce the amount of gray matter and limits our ability to assess the laterality of effects. Second, the relatively small sample size may increase the risk of type II errors. For example, we found a trend level increase in Glx in the dACC in patients than controls (SMD = 0.43 [-0.01–0.87], 