The NMDA receptor antagonist ketamine can induce a rapid improvement in depressive symptoms that often endures for days after a single intravenous dose. The pharmacodynamic basis for this effect is poorly understood. Using a proton magnetic resonance spectroscopy ([ 1 H]-MRS) method that previously detected a normalization of amino acid neurotransmitter (AANt) content after chronic treatment with conventional antidepressant treatments, we examined whether the acute action of ketamine is associated with alterations in AANt content as well. Ten subjects with major depressive disorder (MDD) received saline, then ketamine in a fixed order, one week apart, under single-blind conditions. Each infusion was associated with three [ 1 H] MRS scans (baseline, 3 hours and 48 hours post-infusion) that measured glutamate, GABA and glutamine within the occipital cortex. Rating scales were administered before, during and after each infusion. The rapid (1 hour) and sustained (at least 7 days) antidepressant effect we observed after ketamine infusion was not associated with either baseline measures of, or changes in, occipital AANt content. Dissociative symptoms were not correlated with changes in depression scores. While our results indicate that changes in occipital AANt content are not a correlate of ketamine's antidepressant action, this may only apply to the regional and temporal windows of our MRS measurements.

Proton magnetic resonance spectroscopy ( 1 HMRS) is an in vivo brain imaging method that can be used to investigate psychotropic drug mechanism of action. This study evaluated baseline 1 HMRS spectra of bipolar depressed patients and whether the level of cerebral metabolites changed after an open trial of lamotrigine, an anti-glutamatergic mood stabilizer. Twenty-three bipolar depressed and 12 control subjects underwent a MRS scan of the anterior cingulate/medial prefrontal cortex. The scan was performed on a GE whole-body 1.5 T MRI scanner using single-voxel PRESS (TE/TR ¼ 30/3000 ms, 3 Â 3 Â 3 cm 3 and post-processed offline with LCModel. Baseline CSF-corrected absolute concentrations of glutamate + glutamine ([Glx]), glutamate ([Glu]), and creatine + phosphocreatine ([Cr]) were significantly higher in bipolar depressed subjects vs healthy controls. The non-melancholic subtype had significantly higher baseline [Glx] and [Glu] levels than the melancholic subtype. Remission with lamotrigine was associated with significantly lower post-treatment glutamine ([Gln]) in comparison to non-remission. These data suggest that non-melancholic bipolar depression is characterized by increased glutamate coupled with increased energy expenditure. Lamotrigine appears to reduce glutamine levels associated with treatment remission. Further study is encouraged to determine if these MR spectroscopic markers can delineate drug mechanism of action and subsequent treatment response.

Background Ethanol modulates glutamate and GABA function. However, little is known about the acute pharmacologic effects of ethanol on levels of GABA, glutamate, and other metabolites measurable in the human cortex in vivo using 1H magnetic resonance spectroscopy (MRS). Methods Eleven healthy social drinkers received two intravenous ethanol infusions that raised breath alcohol levels to a clamped plateau of 60 mg/dL over 60–70 minutes. The first infusion established tolerability of the procedure, and the second procedure, conducted 15±12 days later, was performed during 1H MRS of occipital GABA, glutamate, and other metabolites. Results The time course of brain ethanol approximated that of breath ethanol, but venous ethanol lagged by about 7 minutes. GABA fell 13±8% after 5 minutes of the ethanol infusion and remained reduced (p=0.003) throughout the measurement. The combination of N-acetylaspartate and N-acetylaspartyl glutamate (summed as NAA) fell steadily during the infusion by 8±3% (p=0.0036). Conclusions Ethanol reduced cortical GABA and NAA levels in humans. Reductions in GABA levels are consistent with facilitation of GABAA receptor function by ethanol. The gradual decline in NAA levels suggests inhibition of neural or metabolic activity in the brain.

Purpose: To measure cerebral metabolites in brains of human immunodeficiency virus (HIV)-infected patients using two-dimensional (2D) proton ( 1 H) magnetic resonance spectroscopy (MRS), which enables more sensitive detection of metabolites at lower concentrations and delineation of the components of the different choline (Ch) groups in the frequency domain when compared to one dimensional (1D) 1 H-MRS. Materials and Methods:We examined metabolite/creatine (Cr) and metabolite/Ch ratios in the left frontal brain of 10 HIV-infected (mean age 13.7 Ϯ 4.7 years) and 11 control (mean age 15.3 Ϯ 4.6 years) adolescents and children using 2D localized chemical shift correlated spectroscopy (L-COSY). The integrated volume under each 2D metabolite peak was calculated with reference to the diagonal creatine methyl peak (Cr_d) or the diagonal choline trimethylamine peak (Ch_d). Results:In the HIV-infected patients, myoinositol (mI)/ Cr_d (P ϭ 0.009) and mI/Ch_d (P ϭ 0.006) were elevated. The ratios of the following metabolites were also significantly elevated (P Ͻ 0.05): mI-Ch/Cr_d, ␥-aminobutyrate (GABA)/ Cr_d , GABA/Ch_d, threonine-lactate (Thr-Lac)/ Cr_d, Thr-Lac/Ch_d, and N-acetyl aspartate (NAA)/Cr_d. Conclusion:We have demonstrated for the first time the feasibility of 2D-MRS in HIV-infected children and adolescents to assess cerebral metabolites and found elevated mI and elevated GABA, in the left frontal brain of clinically stable HIV-infected patients. A larger study population is needed to confirm these pilot GABA findings.

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The relationship between the logarithm of retention indices (log k IAM ) of 55 diverse drugs in immobilized artificial membrane (IAM) chromatography and molecular structure descriptors was established by linear and non-linear modeling methodsProjection Pursuit Regression (PPR) and lazy learning method-Local Lazy Regression (LLR). The descriptors calculated from the molecular structures by the software CODESSA and a widely accepted property parameter ClogP were used to represent the characteristics of the compounds. The best multi-linear regression (BMLR) method in the CODESSA was used to select the most important molecular descriptors from a large set of descriptors and to develop the linear and non-linear quantitative structure retention relationship (QSRR) models. By comparing these different methods, the LLR model gave the best predictive results for the drugs studied in the present work with the square of correlation coefficient (R 2 ) of 0.9540, 0.9305; root mean square error (RMSE) of 0.2418, 0.3949; for the training set and test set, respectively. It was proved that the LLR method was a promising method for QSRR modeling with good predictive capability for the retention indices of drugs in immobilized artificial membrane chromatography, and could be used in other similar chromatography research fields.