A placebo-controlled trial of acetyl-L-carnitine and α-lipoic acid in the treatment of bipolar depression.

BACKGROUND: Bipolar disorder may be associated with mitochondrial dysfunction. Therefore, agents that enhance mitochondrial functioning may be efficacious in bipolar disorder. We performed a randomized placebo-controlled trial of the mitochondrial enhancers acetyl-L-carnitine (ALCAR) and α-lipoic acid (ALA) in patients with bipolar depression, and assessed markers of cerebral energy metabolism using phosphorus magnetic resonance spectroscopy. METHODS: We administered ALCAR (1000-3000 mg daily) plus ALA (600-1800 mg daily) or placebo for 12 weeks to 40 patients with bipolar depression and obtained imaging data at baseline, week 1, and week 12 of treatment in 20 patients using phosphorus 3-dimensional chemical-shift imaging at 4 T. Statistical analysis used random effects mixed models. RESULTS: We found no significant difference between ALCAR/ALA and placebo on change from baseline in the Montgomery-Asberg Depression Rating Scale in both the longitudinal (mean difference [95% confidence interval], -1.4 [-6.2 to 3.4], P = 0.58) and last-observation-carried-forward (-3.2 [-7.2 to 0.9], P = 0.12) analyses. ALCAR/ALA treatment significantly reduced phosphocreatine levels in the parieto-occipital cortex at week 12 (P = 0.002). Reduction in whole brain total nucleoside triphosphate levels from baseline to week 1 was associated with reduction in Montgomery-Asberg Depression Rating Scale scores (P = 0.02) in patients treated with ALCAR/ALA. However, this was likely a chance finding attributable to multiple statistical comparisons. CONCLUSIONS: Treatment with ALCAR and ALA at the dose and duration used in this study does not have antidepressant effects in depressed bipolar patients and does not significantly enhance mitochondrial functioning in this patient group.

GABA levels in the dorsal anterior cingulate cortex associated with difficulty ignoring smoking-related cues in tobacco-dependent volunteers.

Substance abusers have difficulty ignoring drug-related cues, which is associated with relapse vulnerability. This 'attentional bias' towards drug cues translates into an inability to ignore drug-related stimuli and may reflect deficits in the brain regions, such as the dorsal anterior cingulate cortex (dACC)-a key region in cognitive control and adaptive decision making. Quantifying relationships between attentional biases to drug cues and dACC neurochemistry could aid in identifying neurobiological mechanisms associated with increased relapse vulnerability precipitated by drug cues. As gamma-aminobutyric acid (GABA) deficits have been linked to impaired cognition and addictive disorders, we hypothesized that reduced GABA in the dACC would be associated with increased attentional biases towards smoking-related cues. We confirmed this hypothesis among nicotine-dependent tobacco smokers by combining an offline behavioral measure of attentional bias with magnetic resonance spectroscopy. Smokers with the greatest attentional bias also experienced more negative affect during early nicotine withdrawal. Findings revealed a relationship between heightened reactivity to drug cues, and both decreasing dACC GABA and early withdrawal symptoms. Because reduced GABA function in frontal brain regions disrupt cognitive function, our findings suggest that smokers with diminished dACC GABA may lack the cognitive resources to successfully ignore highly salient distractors such as tobacco-related stimuli and therefore might be more prone to cue-induced relapse. This newly discovered relationship between dACC GABA and attentional bias provides evidence for a neurochemical target, which may aid smoking cessation in highly cue-reactive individuals.

Preliminary evidence for white matter metabolite differences in marijuana-dependent young men using 2D J-resolved magnetic resonance spectroscopic imaging at 4 Tesla.

Chronic marijuana (MRJ) use is associated with altered cognition and mood state, altered brain metabolites, and functional and structural brain changes. The objective of this study was to apply proton magnetic resonance spectroscopic imaging (MRSI) to compare proton metabolite levels in 15 young men with MRJ dependence and 11 healthy non-using (NU) young men. Spectra were acquired at 4.0 Tesla using 2D J-resolved MRSI to resolve coupled resonances in J-space and to quantify the entire J-coupled spectral surface of metabolites from voxels containing basal ganglia and thalamus, temporal and parietal lobes, and occipital white and gray matter. This method permitted investigation of high-quality spectra for regression analyses to examine metabolites relative to tissue type. Distribution of myo-inositol (mI)/creatine (Cr) was altered in the MRJ group whereas the NU group exhibited higher mI/Cr in WM than GM, this pattern was not observed in MRJ subjects. Significant relationships observed between global mI/Cr and distribution in WM, and self-reported impulsivity and mood symptoms were also unique between MRJ and NU groups. These preliminary findings suggest that mI, and distribution of this glial metabolite in WM, is altered by MRJ use and is associated with behavioral and affective features reported by young MRJ-dependent men.