Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Feature Article Mitochondrial Dysfunction and New Therapeutic Targets in Bipolar Affective Disorder Iveta Fizikova, MD; and Jozef Dragasek, MD, PhD, MSc, MHA Bipolar affective disorder (BAD) is a complex illness encompassing varying degrees of fluctuating disturbances of emotions, behavior, thought, cognition, and hedonic and motoric drive over the course of a patient’s life. Mitochondrial dysfunction may play an important role in the pathophysiology of BAD. Mitochondrial dysfunction may explain the repeatedly observed changes in the brain of patients with BAD. In BAD, studies of peripheral blood cells have shown changes in antioxidant enzymes, increased lipid peroxidation, elevated levels of reactive nitrogen species, and increased DNA and RNA fragmentation. Early intervention is important in slowing the progression of BAD. Not all patients respond to treatment in the same way, but new treatments are expected to address these clinical challenges. This article reviews the hypothesis of mitochondrial dysfunction and provides a new perspective on therapeutic targets in BAD. [Psychiatr Ann. 2017;47(2):100-104.] © Shutterstock ABSTRACT M ood disorders such as bipolar affective disorder (BAD) are severe, chronic, and disabling psychiatric conditions commonly associated with persistent subsyndromal symptoms and frequent episodic relapses. In addition, some studies1,2 support the notion that mood disorders are heterogeneous conditions with a wide range of clinical features. Iveta Fizikova, MD, is a Psychiatrist, Psychiatric Hospital of Professor Matulay. Jozef Dragasek, MD, PhD, MSc, MHA, is an Assistant Professor of Psychiatry, 1st Department of Psychiatry, Pavol Jozef Safarik University. Address correspondence to Jozef Dragasek, MD, PhD, MSc, MHA, 1st Department of Psychiatry, Pavol Jozef Safarik University, Faculty of Medicine, Trieda SNP 1, 040 11, Kosice, Slovakia; email: [email protected]. Disclosure: The authors have no relevant financial relationships to disclose. doi: 10.3928/00485713-20170103-01 100 It has been increasingly recognized that people with BAD are at a higher risk for chronic general medical conditions, such as obesity, diabetes mellitus, and cardiovascular diseases, which, in turn, are directly associated with the increased morbidity and mortality observed in BAD.1 MITOCHONDRIAL DYSFUNCTION IN BIPOLAR AFFECTIVE DISORDER Mitochondrial physiology is a source of energy production. One of the byproducts of oxidative phosphorylation is the production of reactive oxygen species (ROS), which are capable of reacting with a wide variety of biological substrates, including proteins, membrane lipids, and nucleic acids, leading to cell damage and mutations. Copyright © SLACK Incorporated Feature Article Kato et al.2 anticipated some of the recent developments in the field when they first proposed that mitochondrial dysfunction might play an important role in the pathophysiology of BAD. Recently, there has been an increasing number of studies3,4 dealing with the biochemical aspects of this disorder. Results are based primarily on studies5,6 in which magnetic resonance spectroscopy was used to show some abnormalities of energy metabolism or improvement by treatment. Table 1 shows the changes in brain concentrations of certain molecules in people with BAD.7,8 OXIDATIVE STRESS AND BIPOLAR AFFECTIVE DISORDER Oxidative damage results from an overproduction of ROS that overwhelms cellular antioxidant capacity. Brain cells are more vulnerable than other cells to oxidative damage. This is because the brain, although it constitutes less than 2% of total body weight, consumes approximately 20% of the body’s total oxygen. Studies of peripheral blood cells in BAD have shown changes in antioxidant enzymes, increased lipid peroxidation, elevated levels of reactive nitrogen species, and increased DNA and RNA fragmentation.3 ANTIOXIDANT ENZYMES AND PROTEIN DAMAGE In a study3 that focused on the glutathione system (glutathione peroxidase [GPX], glutathione reductase [GR], and glutathione-S-transferase [GST]) and protein damage, activity of GR and GST was increased and 3-nitrotyrosine levels were elevated in patients with late-stage BAD (10-20 years of illness), compared with healthy participants. In patients with early-stage BAD (0-3 years), only an elevation of 3nitrotyrosine levels was found. PSYCHIATRIC ANNALS • Vol. 47, No. 2, 2017 Protein oxidation, assessed as the level of carbonylation and GPX activity, did not differ significantly between patients in the early and late phases of BAD and healthy controls. LIPID PEROXIDATION Increased lipid peroxidation and decreased activity of the antioxidant defense enzymes (superoxide dismutase and catalase) have been found in the plasma of patients with BAD.3,9 Additionally, the expression of the antioxidant enzyme GST A4 and M3 subtypes was found to be reduced in postmortem brain samples from patients with BAD.9 DAMAGE TO DNA AND RNA ROS react not only with lipids and proteins but also with nucleic acids, thereby inducing oxidative damage to DNA and RNA. Guanine in DNA and RNA is more sensitive to ROS attacks than are the other bases. ROS oxidize guanine and generate 8-oxo-7,8dihydroguanosine (8-OHG) in RNA and 8-oxo-7,8-dihydro-2-deoxyguanosine (8-OHdG) in DNA. These findings suggest that the process of oxidative damage may play an important role in the pathology of BAD.9,10 BIPOLAR AFFECTIVE DISORDER AND INFLAMMATION Studies11,12 have shown that patients in the early and late phases of BAD have elevated levels of proinflammatory cytokines (interleukin [IL]-1, IL-2, IL-6, and tumor necrosis factor-alpha) compared with healthy controls. Increased anti-inflammatory IL-10 was documented only in patients with early-stage disease.3 This suggests that the long-term course of BAD is associated with disturbed anti-inflammatory defense. Proinflammatory cytokines increase the activity of the hypothalamicpituitary-adrenal (HPA) axis, which TABLE 1. Changes in Brain Concentrations of Certain Molecules in Patients with Bipolar Affective Disorder Molecule Change N-acetylaspartate Decrease7,8 Glutamate/glutamine Increase7,8 Compounds containing choline Increase7,8 Myo-inositol Increase7,8 Lactate Increase7,8 Creatine phosphate Decrease8 Phosphate monoesters Increase8 Intracellular pH Decrease7,8 causes production of free radicals. IL-1 plays a key role in the activation of the HPA. Induction of BAD by cytokines may be due to their effect on serotonergic, noradrenergic, glutamatergic, and HPA systems. For example, proinflammatory cytokines activate indoleamine-2,3dioxygenase, which degrades serotonin and tryptophan. Pterin released from macrophages is an important factor that connects the immune and nervous systems. Production of neopterin is associated with increased degradation of tryptophan (a precursor of serotonin). Tetrahydrobiopterin is an essential cofactor of hydroxylase of tyrosine and tryptophan (the rate-limiting enzyme of biosynthesis of serotonin, noradrenaline, and dopamine), as well as nitric oxide synthase. Elevated plasma concentrations of neopterin and decreased concentration biopterin have been found in patients in the depressive phase of BAD.11,12 101 Feature Article THE ROLE OF DOPAMINE IN THE OXIDATIVE STRESS ASSOCIATED WITH BIPOLAR AFFECTIVE DISORDER Increased levels of dopamine is associated with symptoms of mania. Conversely, reducing dopamine transmission, or reducing dopamine synthesis or blockade of dopamine D2 receptors, is responsible for the antimanic effect. Interestingly, the increased level of dopamine is an important initiator of oxidative stress in the brain because of its oxidative metabolism. 6-Hydroxydopamine is toxic to the nervous system. Mechanisms associated with its toxicity include endoplasmic reticulum stress, activation of glycogen synthase kinase-3-beta phosphorylation on tyrosine 216, and inhibition of protein kinase B phosphorylation on serine 473.3 THERAPEUTIC TARGETS FOR MOOD DISORDERS Delay in initiation of appropriate forms of therapy in the early stages of BAD can cause significant functional impairment. Recently, a number of studies3,13 have shown that mood-stabilizing drugs and antipsychotic drugs inhibit oxidative damage and increase activity of various antioxidant enzymes, suggesting that the process of oxidative damage may be targeted by these drugs.1 MITOCHONDRIA AS NEW THERAPEUTIC TARGETS FOR MOOD DISORDERS New treatments are expected to address clinical challenges and be more effective, better tolerated, and act faster than currently available treatments. N-acetyl Cysteine Altered levels of glutathione, the most abundant antioxidant substrate in all tissues, have been described in patients with BAD.14 Treatment with N-acetyl cysteine (NAC), a precursor of gluta102 thione, increases glutathione levels.15 A recent randomized, double-blind, multicenter, placebo-controlled study involving 75 patients with BAD evaluated the effect of the treatment with NAC (1 g twice a day) as an addition to usual treatment during a period of 24 months.13 New treatments are expected to address clinical challenges and be more effective, better tolerated, and act faster. This was followed by a 4-week washout phase. By the end of the study, NAC showed superior antidepressant effects compared to placebo, as assessed by Montgomery Asberg Depression Rating Scale scores and most secondary scale scores. It is interesting to note that the patients were not necessarily selected for having a major depressive episode. The authors hypothesized that the efficacy of NAC might be due to its ability to reverse increased oxidative stress during episodes of high or low moods.13 Creatine Creatine plays a key role in brain energy homeostasis, and its dysfunction has been shown to be implicated in BAD.16 Brain creatine kinase has been shown to be altered in the hippocampus in animal models of mania as well as in patients with BAD during a manic episode.13 Thus, creatine supplementation may modify brain high-energy phosphate metabolism in people with BAD. Recently, an open-label study16 involving 10 treatment-resistant patients with depression (two of whom had BAD) found that 3 to 5 mg/day of creatine monohydrate added to the ongoing treatment led to a significant improvement in depressive symptoms in the patients with major depressive disorder; however, the two patients with BAD experienced transient hypomanic/manic symptoms. Glycogen Synthase Kinase-3 Glycogen synthase kinase-3 (GSK-3) is an important regulator of glycogen synthesis, gene transcription, synaptic plasticity, apoptosis, cellular structure, and resilience. It has been suggested that GSK-3 regulates behavior by affecting beta-catenin, glutamate receptors, circadian rhythms, and serotonergic neurotransmission. All of these have been found to be implicated in the pathophysiology of severe mood disorders.4 Lithium has been shown to target GSK-3-beta in several paradigms.13 Lithium also induces neurotrophic and neuroprotective effects in rodents, partly due to GSK-3-beta inhibition. Valproate was initially reported to inhibit GSK3-beta activity in SH-SY5Y cells;17 however, these effects have not been confirmed in neuronal cells. Carbamazepine was reported to be involved in signal transduction of cyclic adenosine monophosphate secondmessenger systems;13 however, no effect on Akt/GSK-3-beta has been reported to date. Inhibition of GSK-3-beta is associated with some limitations due to its involvement with diverse pathways that contain multiple substrates, which may lead to side effects or toxicity. At the time of this writing, no GSK-selective inhibitors that can cross the bloodbrain barrier have been clinically tested. Proof-of-principle studies focused on selective and safe GSK-3-beta inhibitors are needed to establish the potential reliability and therapeutic relevance of this group of inhibitors in mood disorders.4 Protein Kinase C Signaling Cascade Protein kinase C (PKC) plays an important role in regulating neuronal excitability, neurotransmitter release, and Copyright © SLACK Incorporated Feature Article long-term alterations in gene expression and plasticity. Some of the studies18 show that PKC is regulated by the mood stabilizers lithium and valproate. Two recent clinical trials19,20 provide further evidence for the involvement of this system in bipolar mania. Although well known for its anti-estrogenic properties, tamoxifen is also a potent PKC inhibitor at high concentrations. In all cases, the antimanic effects of tamoxifen were not shown to be related to its sedative effects, and no increased risk of depression was observed.13 However, it is possible that some of tamoxifen’s antimanic effects may be due to its antiestrogen properties. It is also important to note that other drugs tested in patients with BAD, such as omega-3 fatty acids and verapamil, inhibit PKC activity, which reinforces the role of this target in developing medications for BAD. For instance, verapamil showed significant antimanic effects when combined with lithium in a double-blind, randomized study.21 Histone Deacetylases Histone acetylation has been considered as promising therapeutic target in mood disorders because of its ability to control epigenetic effects that regulate cognitive and behavioral processes. Histone acetylation reduces histones’ affinity for DNA and is a major epigenetic regulator of gene expression for several key proteins. Thus, diverse histone deacetylase (HDAC) inhibitors that could serve as novel neuroprotective agents have been developed. Their ability to affect neuronal function and protection occurs largely through epigenetic mechanisms. Furthermore, it has been suggested that central nervous systempenetrant HDAC inhibitors may eventually have potential therapeutic relevance in mood disorders, supposedly due to their ability to reverse dysfunctional epigenetic effects associated with PSYCHIATRIC ANNALS • Vol. 47, No. 2, 2017 early life events.22 In neuronal tissue, HDAC inhibitors limit histone deacetylation mostly by inactivating class I or II HDACs, thus increasing histone acetylation. Notably, the mood stabilizer valproate is an HDAC inhibitor, suggesting that its effects at this target may play a therapeutic role in mood stabilization, although it may also be associated with side effects such as teratogenicity or polycystic ovarian syndrome.23 Also, down-regulation of reelin and glutamic acid decarboxylase expression in cortical interneurons in people with BAD may be regulated by epigenetic hypermethylation.22 The same group noted that valproate blocked methionineinduced reelin promoter hypermethylation and reelin mRNA downregulation, thus improving social interaction in preclinical models.24 The Melatonergic System Melatonin is expected to protect cells by preventing mitochondrial injury and thus preserve membrane potential and the energy-producing function (adenosine triphosphate levels) of mitochondria. Melatonin receptors MT1 and MT2 are highly expressed in the brain and induce biological effects mostly through G protein–coupled receptors. Supersensitivity to melatonin suppression by light was described in people with mood disorders and their unaffected offspring.13 A recent, open-label, 6-week study25 in 21 people with bipolar depression assessed the effects of agomelatine (25 mg/day), a nonselective MT1 and MT2 receptor agonist. Approximately 81% of patients achieved significant improvement at endpoint, and 47% showed response during the first week of treatment. In preclinical models, agomelatine had significant antidepressant-like effects in the forced swim test, the chronic mild stress test, and the learned helplessness paradigm.26 It was also capable of resynchronizing a disrupted circadian rhythm and had circadian phaseadvancement properties. Agomelatine is also known to increase the amount of both norepinephrine and dopamine, and to increase cell proliferation and neurogenesis in the ventral dentate gyrus. Thus, a growing body of evidence supports a relevant role for melatonergic modulators as therapeutics for major depressive disorder, especially its neurovegetative symptoms.27 CONCLUSION The hypothesis of mitochondrial dysfunction may explain the repeatedly observed changes in the brain of patients with BAD. Early intervention is important in slowing the progression of BAD. Not all patients react to treatment in the same way. For instance, lower response rates are seen in patients with rapid cycling, as well as in those presenting with a greater number of psychiatric comorbidities or suicidality. This is why new treatments are expected to address today’s clinical challenges. It is critical to the health of patients that the next generation of treatments for mood disorders be more effective, better tolerated, and act faster than currently available treatments.1,11 REFERENCES 1. Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet. 2016;387(10027):15611572. 2. Kato T. Neurobiological basis of bipolar disorder: mitochondrial dysfunction hypothesis and beyond. Schizophr Res. 2016; pii: S0920-9964(16)30481-9. doi: 10.1016/j. schres.2016.10.037. [Epub ahead of print]. 3. Andreazza AC, Kapczinski F, KauerSant’Anna M, et al. 3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder. J Psychiatry Neurosci. 2009;34:263-271. 4.Gould TD, Zarate CA, Manji HK. Glycogen synthase kinase-3: a target for novel bipolar disorder treatments. J Clin Psychiatry. 2004;65:10-21. 5. Dudley JA, Lee, JH, Durling M, et al. Age-dependent decreases of high energy phosphates in cerebral gray matter of patients with bipolar I disorder: a preliminary phosphorus-31 103 Feature Article magnetic resonance spectroscopic imaging study. J Affect. Disord. 2015;175:251-255. 6. Shi XF, Carlson PJ, Sung YH, et al. Decreased brain PME/PDEratio in bipolar disorder: a preliminary (31) P magnetic resonance spectroscopy study. Bipolar Disord. 2015;17(7):743-752. 7. Maddock RJ, Buonocore MH. MR spectroscopic studies of the brain in psychiatric disorders. Curr Top Behav Neurosci. 2012;11:199-251. 8. Stork C, Renshaw PF. Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol Psychiatry. 2005;10(10):900-919. 9.Tuncel OK, Sarisoy G, Bilgici B, et al. Oxidative stress in bipolar and schizophrenia patients. Psychiatry Res. 2015;228(3):688-694. 10. Che Y, Wang JF, Shao L, et al. Oxidative damage to RNA but not DNA in the hippocampus of patients with major mental illness. J Psychiatry Neurosci. 2010;35(5):296-302. 11.Rosenblat JD, Brietzke E, Mansur RB, Maruschak NA, Lee Y, McIntyre RS. Inflammation as a neurobiological substrate of cognitive impairment in bipolar disorder: evidence, pathophysiology and treatment implications. J Affect Disord. 2015;188:149-159. 12.Morris G, Berk M. The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders. BMC Med. 2015;1(13):68. doi: 10.1186/s12916-0150310-y. 104 13. Machado-Vieira RM, Salvadore G, Granados ND, et al. New therapeutic targets for mood disorders. Sci World J. 2010;10:713-726. 14. Andreazza AC, Kauer-Sant’anna M, Frey BN, et al. Oxidative stress markers in bipolar disorder: a meta-analysis. J Affect Disord. 2008;111(2-3):135-144. 15. Deepmala D, Slattery J, Kumar N, et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: a systematic review. Neurosci Biobehav Rev. 2015;55:294-321. 16.Streck EL, Amboni G, Scaini G, et al. Brain creatine kinase activity in an animal model of mania. Life Sci. 2008;82:424-429. 17. Chuang DM. The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. Ann N Y Acad Sci. 2005;1053:195-204. 18. Hahn CG, Friedman E. Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder. Bipolar Disord. 1999;1:81-86. 19. Yildiz A, Guleryuz S, Ankerst DP, Ongür D, Renshaw PF. Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen. Arch Gen Psychiatry. 2008;65(3):255-263. 20. Zarate CA Jr, Singh JB, Carlson PJ, et al. Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. Bipolar Disord. 2007;9:561-570. 21.Abrial E, Etievant A, Betry C, et al. Protein kinase C regulates mood-related behaviors and adult hippocampal cell proliferation in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2013;43:40-48. 22.Grayson DR, Kundakovic M, Sharma RP. Is there a future for histone deacetylase inhibitors in the pharmacotherapy of psychiatric disorders? Mol Pharmacol. 2010;77:126-135. 23. Phiel CJ, Zhang F, Huang EY, et al. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem. 2001;276(39):3673436741. 24. Guidotti A, Auta J, Davis JM, et al. Decrease in reelin and glutamic acid decarboxylase 67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry. 2000;57(11):10611069. 25. Calabrese JR, Guelfi JD, Perdrizet-Chevallier C. Agomelatine adjunctive therapy for acute bipolar depression: preliminary open data. Agomelatine Bipolar Study Group. Bipolar Disord. 2007;9(6):628-635. 26. Bertaina-Anglade V, la Rochelle CD, Boyer PA, Mocaer E. Antidepressant-like effects of agomelatine (S 20098) in the learned helplessness model. Behav Pharmacol. 2006;17:703713. 27.De Berardis D, Fornaro M, Serroni N, et al. Agomelatine beyond borders: current evidences of its efficacy in disorders other than major depression. Int J Mol Sci. 2015;16(1):1111-1130. Copyright © SLACK Incorporated