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

Abstract

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.

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

“…A number of agents do not have sufficient data to warrant specific recommendations for BDII depression, including cranial electrotherapy stimulation (CES),479 dextromethorphan + quinidine,480 light therapy,481, 482, 483, 484, 485 lisdexamfetamine (adjunctive),300 olanzapine,486 pioglitazone,302 adjunctive pregnenolone,306 celecoxib,297 levetiracetam,487 adjunctive lisdexamfetamine,300 s‐adenosylmethionine,488, 489, 490 acetyl‐ l ‐carnitine + alpha‐lipoic acid,491 adjunctive modafinil,268 rTMS,275, 492, 493 and memantine 494…”

Perturbational Profiling of Metabolites in Patient Fibroblasts Implicates α-Aminoadipate as a Potential Biomarker for Bipolar Disorder

“…Carnitine is necessary for the transport of long-chain fatty acids into the mitochondrial matrix for generating metabolic energy from lipid breakdown [73]. While there are no studies specifically looking at C4 carnitine in bipolar disorder, carnitine biology in general has been studied in the context of new treatment approaches for bipolar disorder [74,75]. Polymorphisms in a carnitine transporter SLC22A16 are strongly associated with bipolar I disorder [76].…”

Emergent treatments based on the pathophysiology of bipolar disorder: A selective review

“…Acetyl-L-carnitine (ALCAR) is a highly bioavailable compound that is converted to lcarnitine which facilitates lipid metabolism and energy production in mitochondria. The idea that bipolar disorder may be a disorder of mitochondrial dysfunction (and low energy production) led Brennan et al to test ALCAR's efficacy in subjects with bipolar depression (Brennan et al, 2013). Brennan et al conducted a randomized, placebo controlled clinical trial of adding either Acetyl-L-carnitine and α-lipoic acid (to minimize the creation of reactive oxygen species with ALCAR) or placebo to the medication regimen of subjects diagnosed with bipolar disorder (type I or II) that were currently depressed.…”