Contributions of brain glutamate (Glu) to conscious emotion are not well understood. Here, we evaluate the relationship of experimentally induced change in neocortical Glu (ΔGlu) and subjective states in well individuals, using combined application of pharmacological challenge, magnetic resonance spectroscopy (MRS), and comprehensive affective assessment. Drug challenge with d-amphetamine (AMP) (20 mg oral), methamphetamine (MA) (Desoxyn, 20 mg oral), and placebo (PBO) was conducted on three separate test days in a within-subjects double blind design. Proton MRS quantified neurometabolites in the right dorsal anterior cingulate cortex 140-150 min post-drug and PBO. Subjective states were assessed at half hour intervals over 5.5 h on each session, yielding 3792 responses per participant (91,008 responses overall, N = 24 participants), with self-reports reduced by principal components analysis (PCA). PCA produced a primary factor score of AMP- and MA-induced positive agency (ΔPA). MRS indicated drug-induced ΔGlu related positively to ΔPA (ΔGluMA r = +0.44, p < 0.05, N = 21), with large effects in females (ΔGluMA r = +0.52, p < 0.05; ΔGluAMP r = +0.61, p < 0.05, N = 11). Subjective states related to ΔGlu included rise in subjective stimulation, vigor, friendliness, elation, positive mood, positive affect (r\'s = +0.51 to +0.74, p < 0.05), and alleviation of anxiety in females (r = -0.61, p < 0.05, N = 11). These self-reports correlated with ΔGlu to the extent they loaded on ΔPA (r = 0.95 AMP, p = 5 × 10-10; r = 0.63 MA, p = 0.0015, N = 11), indicating the coherence of ΔGlu effects on emotional states. Timing data indicated Glu shaped positive emotion both concurrently and prospectively, with no relationship with pre-MRS emotion (ΔGluAMP r = +0.59 to +0.65, p\'s < 0.05; ΔGluMA r = +0.53, p < 0.05, N = 11). Together these findings indicate substantive, mechanistic contributions of neocortical Glu to positive agentic states in healthy individuals, which are most readily observed in women. The findings illustrate the promise of combined application of pharmacological challenge, comprehensive affective assessment, and MRS neuroimaging techniques in basic and clinical studies.

Effective treatment of negative symptoms is one of the most important unmet needs in schizophrenic disorders. Because the evidence on current psychopharmacological treatments is unclear, the authors reviewed the findings published to date by searching PubMed with the keywords negative symptoms, antipsychotics, antidepressants, glutamatergic compounds, monotherapy and add-on therapy and identifying additional articles in the reference lists of the resulting publications. The findings presented here predominantly focus on results of meta-analyses. Evidence for efficacy of current psychopharmacological medications is difficult to assess because of methodological problems and inconsistent results. In general, the second-generation antipsychotics (SGAs) do not appear to have good efficacy in negative symptoms, although some show better efficacy than first-generation antipsychotics, some of which also demonstrated efficacy in negative symptoms. Specific trials on predominant persistent negative symptoms are rare and have been performed with only a few SGAs. More often, trials on somewhat persistent negative symptoms evaluate add-on strategies to ongoing antipsychotic treatment. Such trials, mostly on modern antidepressants, have demonstrated some efficacy. Several trials with small samples have evaluated add-on treatment with glutamatergic compounds, such as the naturally occurring amino acids glycine and D-serine and new pharmacological compounds. The results are highly inconsistent, although overall efficacy results appear to be positive. The unsatisfactory and inconsistent results can be partially explained by methodological problems. These problems need to be solved in the future, and the authors propose some possible solutions. Further research is required to identify effective treatment for the negative symptoms of schizophrenia.