June 19, 2021
Bipolar disorder is a common psychiatric illness characterized by recurrent episodes of manic and depressive symptoms. It can cause marked disruption in an individual’s life, work, and health. The depressive episodes of bipolar disorder usually dominate the illness and result to significant morbidity and mortality. Pharmacologic treatments include lithium, anticonvulsants, and antipsychotics. In some patients, these may not improve the depressive symptoms, making the treatment more challenging.
Despite decades of extensive research, the etiology and pathogenesis of bipolar disorder remain unclear. Biological hypotheses causing bipolar disorder include neuro-inflammation, neurodegeneration, and mitochondrial dysfunction. Under normal circumstances, the mitochondria generate most of the energy of the brain by oxidative phosphorylation.
Alterations in the gene patterns associated with mitochondrial activity are found in the brain and lymphocytes of patients with bipolar disorder. Moreover, there is an increase in lactate, a product of glycolysis rather than oxidative phosphorylation, and a decrease in phosphocreatine, a high energy storage molecule. Both suggest a mitochondrial disorder.
L-carnitine is an amino acid derivative synthesized from lysine and methionine. It facilitates fatty acid oxidation and mitochondrial production of the energy-giving molecule, adenosine triphosphate (ATP). It enables movement of fatty acids from the cytosol into the mitochondria and the breakdown of fatty acid chains for energy.
Alpha-lipoic acid (ALA) is an antioxidant and a metal chelator. It increases the levels of glutathione, raises hepatocyte ascorbate levels, downregulates nuclear factor kappa-light-chain-enhancer of activated B cells, promotes uptake of glucose by increasing GLUT4 levels and insulin action. L-carnitine and alpha-lipoic acid are known to have beneficial effects in mitochondrial dysfunction in bipolar disorder.
The study of Kato, T., et al in 2010 showed that mitochondrial dysfunction may contribute to bipolar disorder. Evidences regarding the effect of mitochondrial dysfunction contributing to bipolar disorder include: (1) abnormalities in neurochemical markers of cerebral energy metabolism on both proton and phosphorous magnetic resonance spectroscopy (MRS), (2) decreased expression of nuclear genes encoding for proteins involved in mitochondrial energy production on postmortem examination of hippocampal tissue, (3) decreased lymphocytic expression of genes regulating oxidative phosphorylation, (4) abnormal mitochondrial morphology and distribution on postmortem examination of neurons and glia, and (5) elevated lactate levels in cerebrospinal fluid.
Veronese, N., et al. in 2017, conducted a systematic review and meta-analysis on acetyl-L-carnitine (ALCAR) supplementation in the treatment of depressive symptoms. Eligible studies were randomized clinical trials of ALCAR alone or in combination with antidepressant medications with a control group taking placebo or antidepressants. The study showed that there is a significant difference in the decrease in depressive symptoms between ALCAR supplementation and placebo. Moreover, ALCAR appears to have a similar effect to some common antidepressant agents with significantly fewer side effects.
Cekici, H., et al. in 2018, conducted a review study on the potential therapeutic effect of ALA in psychiatric and neurological diseases. Thirty-four research articles related to ALA and the nervous system were included in the study. The study showed that ALA has beneficial effects on neurological diseases including multiple sclerosis, Alzheimer disease, Parkinson disease, and psychiatric disorders such as depression, schizophrenia, and anxiety. Depression is associated with free radicals and oxidative balance in the brain. ALA, a priming substance for the treatment of depression, increases the levels of glutathione in the brain.
A systematic review of mitochondrial agents for bipolar disorder was conducted by Pereira, C., et al in 2017. The study included systematic reviews, randomized controlled trials, observational studies, case series, and animal studies emphasizing agents aiming to target mitochondrial function in bipolar disorder. Mitochondrial agents include N-acetylcysteine, coezyme Q10, alpha-lipoic acid, acetyl-L-carnitine, S-adenosylmethionine, creatine monohydrate, melatonin, pyrimidines, choline, and vitamins A, C, D, B, and E. The study concluded that the compounds were overall well tolerated and have generally benign side-effect profiles. Hence, research for potential treatments targeting mitochondrial function may be a beneficial approach to future treatments.
Abnormal mitochondrial function may cause bipolar disorder. Certain bipolar disorders respond poorly to treatment because mitochondrial dysfunction compromises cerebral energy metabolism. Treatments that enhance mitochondrial function therefore are important in the therapeutic approach of bipolar disorder. This study discussed the effectiveness of the combination of ALCAR and ALA in treating bipolar disorder.
The randomized placebo control trial aims to determine the effectiveness of mitochondrial enhancers, ALCAR and ALA in patients with bipolar depression, and to assess markers of cerebral energy metabolism using phosphorus magnetic resonance spectroscopy (P-MRS).
In 2013, Brennan, B., et al. conducted a randomized, placebo-controlled, double-blind study. Participants recruited were 18 to 55 years old, meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for bipolar disorder (type I or II), currently depressed, with scores greater than or equal to 20 on the Montgomery-Asberg Depression Rating Scale (MADRS) at screening and baseline.
Sixty-eight participants signed informed consent for the study from September 4, 2008 to January 25, 2011. Twenty-eight participants who did not meet the inclusion criteria were withdrawn from the study. Majority of participants who met the inclusion criteria were non-Hispanic white (n = 38) and the remaining were African American (n = 2).
Excluded in the study were individuals with inability to provide written informed consent, history of schizophrenia or obsessive-compulsive disorder, active psychosis, active suicidality, alcohol or substance dependence (except nicotine) within 3 months of enrollment, electroconvulsive therapy within 3 months of enrollment, positive urine drug screen for substances of abuse, history of mitochondrial disorder, current pregnancy or lactating, and history of seizure disorder, organic brain disease, or clinically significant medical disease. For the imaging component of the study, only type 1 bipolar disorder is included to limit heterogeneity of the imaging sample. Patients currently taking psychiatric medications were included in the study provided they had been on stable doses for at least 4 weeks before enrollment and required no significant dose modifications during the study.
Eligible participants to ALCAR/ALA or placebo were assigned in a 1:1 ratio, via a computer-generated randomization schedule. ALCAR and ALA or matching placebo capsules were placed in numbered bottles and were assigned to study participants at randomization. ALCAR (1000–3000 mg daily) plus ALA (600–1800 mg daily) or placebo for 12 weeks was administered to 40 patients with bipolar depression. There was no significant difference on the mean scores on the MADRS over 12 weeks of treatment with ALCAR plus ALA or placebo.
Twenty subjects (10 receiving ALCAR/ALA, 10 receiving placebo) participated in the imaging component of the study, which was obtained at baseline, week 1, and week 12 of treatment. Because of attrition, only 12 (5 ALCAR/ALA and 7 placebo) yielded complete imaging data sets. There was no significant change from baseline in metabolite or pH levels including a posteriori analysis of changes in total β-nucleotide triphosphate (β-NTP), at week 1 and week 12. There was also no significant association between change in P-MRS measures and change in MADRS in any of the regions examined. The study showed that ALCAR/ALA, at the dose and duration used in the study, does not reduce depressive symptoms nor enhance mitochondrial functioning in depressed bipolar patients.
Several limitations in the study include a small sample size, no restrictions on concomitant medications during the course of the study, inclusion of both type I and type II bipolar disorder in the study which increased the biological heterogeneity of the sample, lack of a non–bipolar disorder comparison group in the imaging study which made it difficult to assess the degree of mitochondrial dysfunction at baseline, and oral administration of ALCAR which should have been tested intravenously due to its nonlinear pharmacokinetics and low bioavailability.
Despite the negative result of the study, it is still ideal to do further research on mitochondrial dysfunction and mitochondrial enhancers which may create future developments in the treatment of bipolar depression.
The study showed that administration of ALCAR plus ALA does not have antidepressant effects in depressed bipolar patients and does not significantly enhance mitochondrial functioning in this patient group.
1. Pereira, C., et al. Mitochondrial Agents for Bipolar Disorder. International Journal for Neuropsychopharmacology. 2018.
2. Andreazza, A., et al. Mitochondrial Complex I Activity and Oxidative Damage to Mitochondrial Proteins in the Prefrontal Complex of Patients with Bipolar Disorder. Journal of the American Medical Association. 2010.
3. Kato, T., et al. Mitochondrial Dysfunction in Bipolar Disorder. Bipolar Disorder. 2000.
4. Cataldo, A., et al. Abnormalities in Mitochondrial Structure in Cells from Patients with Bipolar Disorder. American Journal of Pathology. 2010.
5. Veronese, N., et al. Acetyl-L-Carnitine Supplementation and the Treatment for Depressive Symptoms: A Systematic Review and Meta-analysis. Psychosomatic Medicine. 2017.
6. Cekici, H., et al. Potential Therapeutic Agent in Psychiatric and Neurological Diseases: Alpha Lipoic Acid. Acta Psychopathologica Journal. 2018.
7. Fernandes, R., et al. Acetyl-L-Carnitine for Depression and Mood Disoders. Journal of Integrated Healthcare Practitioners. 2014.