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A Placebo-Controlled Trial of Acetyl-L-Carnitine and α-Lipoic Acid in the Treatment of Bipolar Depression

Brennan, Brian P. MD, MMSc*†‡; Jensen, John Eric PhD†§; Hudson, James I. MD, ScD*†; Coit, Caitlin E. BA*; Beaulieu, Ashley BA*; Pope, Harrison G. Jr MD, MPH*†; Renshaw, Perry F. MD, PhD; Cohen, Bruce M. MD, PhD†‡

Journal of Clinical Psychopharmacology: October 2013 - Volume 33 - Issue 5 - p 627–635
doi: 10.1097/JCP.0b013e31829a83f5
Original Contributions

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.

From the *Biological Psychiatry Laboratory, McLean Hospital, Belmont; †Department of Psychiatry, Harvard Medical School, Boston; ‡Shervert Frazier Research Institute, and §Brain Imaging Center, McLean Hospital, Belmont, MA; and ∥Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT.

Received April 18, 2012; accepted after revision January 2, 2013.

Reprints: Brian P. Brennan, MD, MMSc, McLean Hospital, 115 Mill St, Belmont, MA 02478 (e-mail:

This study was supported by grants from the Stanley Medical Research Institute, the Sidney R. Baer, Jr. Foundation through a NARSAD Young Investigator Award (B.P.B.), and the National Institutes on Drug Abuse (NIDA) Grant T32-DA07252 (B.P.B.). In addition, B.P.B. was supported by the Clinical Investigator Training Program (CITP) through the Beth Israel Deaconess Medical Center-Harvard/MIT Health Sciences and Technology, in collaboration with Pfizer Inc and Merck & Co.

© 2013 by Lippincott Williams & Wilkins.