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

Bipolar disorder is a common and often disabling mental illness. The depressive phase of bipolar disorder frequently dominates the illness and results in significant morbidity and mortality.1 Several pharmacologic treatments including lithium, anticonvulsants, and antipsychotic medications have demonstrated efficacy in the depressed phase of bipolar disorder,2,3 but many patients fail to respond or cannot tolerate first-line mood-stabilizer treatments.4 Furthermore, traditional monoaminergic antidepressant agents may not outperform mood stabilizers alone in such patients.5 Thus, novel treatment strategies for bipolar depression are needed. Recent research suggests that abnormal mitochondrial functioning may contribute to bipolar disorder.6 Although this dysfunction is insufficient to produce a systemic metabolic disorder, it could produce a brain disorder, because the brain requires much larger amounts of energy than other organs.7 Evidence for this hypothesis comes from studies demonstrating a variety of findings in patients with bipolar disorder including (1) abnormalities in several neurochemical markers of cerebral energy metabolism on both proton (1H) and phosphorus (31P) magnetic resonance spectroscopy (MRS)8; (2) decreased expression of nuclear genes encoding for proteins involved in mitochondrial energy production on postmortem examination of hippocampal tissue9; (3) decreased lymphocytic expression of genes regulating oxidative phosphorylation, and impaired up-regulation of genes encoding for proteins of the electron transport chain after exposure to glucose deprivation10; (4) markedly abnormal mitochondrial morphology and distribution on postmortem examination of neurons and glia11; and (5) elevated lactate levels in cerebrospinal fluid (CSF).12 Consequently, certain bipolar patients might respond poorly to current treatments because mitochondrial dysfunction compromises cerebral energy metabolism. Therefore, treatments that enhance mitochondrial functioning may represent a novel therapeutic approach to bipolar disorder. Acetyl-L-carnitine (ALCAR), a naturally occurring mitochondrial metabolite, improves mitochondrial function and energy production in both animals and humans.13–17 Moreover, several placebo-controlled trials have found ALCAR efficacious in various depressive spectrum disorders,18–27 making it an intriguing candidate treatment for the depressed phase of bipolar disorder. However, although ALCAR may increase energy production, it may also increase production of reactive oxygen species28—damaging mitochondrial DNA, proteins, and lipids, and thus further exacerbating defects in energy production. α-Lipoic acid (ALA), a mitochondrial coenzyme, is a potent antioxidant,28 and thus an ideal companion agent with ALCAR to increase mitochondrial metabolic activity without increasing oxidative stress. Indeed, animal studies have demonstrated that the ALCAR/ALA combination improves mitochondrial functioning by increasing metabolism and lowering oxidative stress more than either compound alone28–30 and combined mitochondrial-enhancing compounds have shown more promise than single agents for the treatment of mitochondrial disorders.31 Both ALCAR and ALA easily cross the blood-brain barrier,32,33 possess favorable adverse-effect profiles, and are widely available as over-the-counter supplements, making them especially attractive as potential bipolar disorder treatments. We hypothesized that ALCAR/ALA would demonstrate significantly greater efficacy than placebo as an augmentation treatment in bipolar depressed patients displaying an incomplete response to conventional treatments. Accordingly, we performed a 12-week placebo-controlled, double-blind, parallel-group, flexible-dose study of ALCAR 1000 to 3000 mg daily plus ALA 600 to 1800 mg daily, added to conventional treatment in depressed bipolar patients. Additionally, using 31P-MRS, we assessed in vivo changes in mitochondrial functioning by measuring several biological markers of cerebral energy metabolism during treatment. Specifically, we hypothesized that ALCAR/ALA, but not placebo, at both week 1 and week 12, would produce increased cerebral concentrations of phosphocreatine (PCr), a compound that serves as a reservoir for high-energy phosphates, and β-nucleoside triphosphate (β-NTP), which is widely acknowledged as the best index of brain levels of adenosine triphosphate (ATP). We also hypothesized that ALCAR/ALA treatment would increase cerebral intracellular pH (pH) due to decreased lactate production resulting from a reduced dependence on glycolysis for energy production. Our primary brain region of interest was the anterior cingulate cortex (ACC)—a region implicated in the pathophysiology of bipolar disorder.34,35 We also performed exploratory analyses of the previously mentioned metabolites and pH across the whole brain and in several other brain regions including the parieto-occipital cortex (POC), frontal cortex, and thalamus.