Mitochondrial agents for bipolar disorder
Abstract
Background: Bipolar disorder is a chronic and often debilitating illness. Current treatment options (both pharmaco- and psychotherapy) have shown efficacy, but for many leave a shortfall in recovery. Advances in the understanding of the pathophysiology of bipolar disorder suggest that interventions that target mitochondrial dysfunction may provide a therapeutic benefit. Methods: This review explores the current and growing theoretical rationale as well as existing preclinical and clinical data for those therapies aiming to target the mitochondrion in bipolar disorder. A Clinicaltrials.gov and ANZCTR search was conducted for complete and ongoing trials on mitochondrial agents used in psychiatric disorders. A PubMed search was also conducted for literature published between January 1981 and July 2017. Systematic reviews, randomized controlled trials, observational studies, case series, and animal studies with an emphasis on agents affecting mitochondrial function and its role in bipolar disorder were included. The search was augmented by manually searching the references of key papers and related literature. The results were presented as a narrative review. Results: Mitochondrial agents offer new horizons in mood disorder treatment. While some negative effects have been reported, most compounds are overall well tolerated and have generally benign side-effect profiles. Conclusions: The study of neuroinflammation, neurodegeneration, and mitochondrial function has contributed the understanding of bipolar disorder's pathophysiology. Agents targeting these pathways could be a potential therapeutic strategy. Future directions include identification of novel candidate mitochondrial modulators as well as rigorous and well-powered clinical trials.
Full text
Received: September 27, 2017; Revised: February 11, 2018; Accepted: March 14, 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of CINP. International Journal of Neuropsychopharmacology (2018) 21(6): 550–569 doi:10.1093/ijnp/pyy018 Advance Access Publication: March 27, 2018 Review 550 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] Review Mitochondrial Agents for Bipolar Disorder CíriaPereira MD#, VictorChavarria MD#, JoãoVian MD, Melanie MareeAshton BSc, GDip, MichaelBerk MD, PhD, WolfgangMarx BHealthSci, MDietSt, PhD, and Olivia MayDean BSc (Hons), PhD Psychiatry and Mental Health Department, Centro Hospitalar Lisboa Norte, Lisbon, Portugal (Drs Pereira and Vian); Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (Drs Pereira and Vian); Parc Sanitari San Joan de Déu, Barcelona, Spain (Dr Chavarria); Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, Australia (MsAshton, Dr Berk, and Dr Dean); University of Melbourne, Department of Psychiatry, Royal Melbourne Hospital, Parkville, Australia (MsAshton, Dr Berk, and Dr Dean); Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Australia (MsAshton, Dr Berk, and Dr Dean); Centre for Youth Mental Health, University of Melbourne, Parkville, VIC, Australia (Dr Berk); Deakin University, Food & Mood Centre, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, Australia (Dr Marx). C.P., and V.C. are equal contributors. Correspondence: Olivia Dean, PhD, IMPACT SRC, School of Medicine, Deakin University, HERB Building, P.O. Box 281, Geelong VIC 3220 Australia ([email protected]). Abstract Background: Bipolar disorder is a chronic and often debilitating illness. Current treatment options (both pharmacoand psychotherapy) have shown efficacy, but for many leave a shortfall in recovery. Advances in the understanding of the pathophysiology of bipolar disorder suggest that interventions that target mitochondrial dysfunction may provide a therapeutic benefit. Methods: This review explores the current and growing theoretical rationale as well as existing preclinical and clinical data for those therapies aiming to target the mitochondrion in bipolar disorder. A Clinicaltrials.gov and ANZCTR search was conducted for complete and ongoing trials on mitochondrial agents used in psychiatric disorders. APubMed search was also conducted for literature published between January 1981 and July 2017. Systematic reviews, randomized controlled trials, observational studies, case series, and animal studies with an emphasis on agents affecting mitochondrial function and its role in bipolar disorder were included. The search was augmented by manually searching the references of key papers and related literature. The results were presented as a narrative review. Results: Mitochondrial agents offer new horizons in mood disorder treatment. While some negative effects have been reported, most compounds are overall well tolerated and have generally benign side-effect profiles. Conclusions: The study of neuroinflammation, neurodegeneration, and mitochondrial function has contributed the understanding of bipolar disorder’s pathophysiology. Agents targeting these pathways could be a potential therapeutic strategy. Future directions include identification of novel candidate mitochondrial modulators as well as rigorous and wellpowered clinical trials. Keywords: adjunctive, bipolar disorder, complimentary therapies, mitochondria Significance Statement Box Sample Downloaded from https://academic.oup.com/ijnp/article/21/6/550/4955527 by guest on 11 November 2020
Pereira etal. | 551 Introduction Bipolar disorder (BD) is a complex illness with an approximate prevalence of 1% (Ferrari etal., 2016). It can cause marked disability and social impairment, particularly among people who experience continued subthreshold symptoms between acute phases, with depression being the greatest contributor (Judd etal., 2008). Current pharmacological treatment offers limited efficacy overall, either in preventing relapses or recovery from acute episodes of depression (Perlis et al., 2006). The current treatment for the maintenance phase is mood stabilizers (Chen etal., 1999; Machado-Vieira etal., 2009; Oikawa and Sng, 2016). Antipsychotics and antidepressants are prescribed both in acute phases and maintenance phases, especially when subthreshold symptoms remain. While antipsychotics and mood stabilizers tend to effectively treat mania (Perlis etal., 2006), the treatment of bipolar depression is more challenging, as these agents may not improve depressive symptoms (Calabrese etal., 2007; Sachs et al., 2007), and treatment with antidepressants may induce phase switching, particularly with monotherapy (Post et al., 2006; Viktorin et al., 2014). An additional limitation to effective treatment options is the current lack of understanding of the underlying pathophysiology of bipolar depression (Sigitova et al., 2017). Therefore, several new biological hypotheses are emerging, including neuro-inflammation (Naaldijk etal., 2016), neurodegeneration (Myint and Kim, 2014), and, relevant to the current review, mitochondrial dysfunction (Kato and Kato, 2000; Kato, 2007, 2010). Different lines of evidence implicate mitochondrial impairment in BD. Ahigher prevalence of mood disorders is reported in people with mitochondrial diseases compared to the general population (Fattal etal., 2007). Furthermore, morphological abnormalities and marginal distribution of mitochondria were reported both in postmortem prefrontal cortex samples and peripheral cells from living BD patients. These findings were controlled for lithium treatment (Cataldo etal., 2010). Aplethora of molecular data also confirms abnormal energy metabolism in BD. Indeed, postmortem studies have reported higher lactate concentrations in the brain of people with BD, which suggests a shift from oxidative phosphorylation to glycolysis (Dager etal., 2004). This observation has been supported by similar studies using magnetic resonance spectroscopy (Stork and Renshaw, 2005) and cerebrospinal fluid studies (Regenold et al., 2009). Val66met, a brain-derived neurotrophic factor polymorphism that has been associated with BD, results in lower prefrontal cortex phosphocreatine (PCr) and creatine levels in BD patients (Frey etal., 2007). Electron transport chain complex Iis decreased in both levels and activity in BD patients (Andreazza etal., 2010). Moreover, BD patients downregulate nuclear transcripts for proteins of the entire electron transport chain when subject to glucose deprivation, while controls seem to have the opposite response (Naydenov etal., 2007). There is also robust evidence of increased lipid peroxidation and alterations in calcium metabolism in BD (Munakata et al., 2004; Kato, 2008). Adecrease in the expression of genes regulating oxidative phosphorylation and proteasome degradation in BD patients in comparison to patients with schizophrenia (SZ) and healthy controls was also shown (Konradi etal., 2004). High energy requirements in the brain may also increase the production of reactive oxygen species (ROS), potentially damaging mitochondria themselves, resulting in an exacerbation of mitochondrial energy production failure (Hagen etal., 2002a). Some already approved drugs for BD treatment affect mitochondrial function. Lithium and valproic acid may induce selective complex III and V phosphorylation and increase energy production (Corena-McLeod etal., 2013). Lithium treatment increased electron transport chain complex Iexpression and activity in postmortem brain studies (Sun et al., 2006a). Lithium has also been robustly associated with lower oxidative stress levels (Khairova etal., 2011; Banerjee etal., 2012; de Sousa etal., 2014) and a reversal of mitochondrial calcium alterations (Machado-Vieira etal., 2011). Atypical antipsychotics increase superoxide dismutase gene expression and have antiapoptotic properties (He etal., 2009). As our understanding of the pathophysiology of BD increases, new compounds targeting mitochondrial function are of interest. The aim of this review is to give an update on potential interventions for BD that act via modulation of mitochondrial function (see Table1). Where available, data from randomized controlled trials were preferred. However, where no clinical data exist, data from case reports or open-label studies were also discussed. MitochodrialAgents N-Acetyl Cysteine N-acetyl cysteine (NAC) is increasingly being used as an adjunctive therapy in psychiatry (Berk etal., 2013). Its use across psychiatric disorders is due to the number of mechanisms of action relevant to mental illness. In addition to providing rate-limiting cysteine for glutathione production, NAC has also been shown to be an antiinflammatory, enhance neurogenesis, decrease apoptosis, modulate glutamate pathways, and, importantly, alter mitochondrial activity (Samuni etal., 2013). In both mouse (R6/1) and rat (3-nitropropionic acid) models of Huntington’s Disease, NAC has been shown to restore mitochondrial respiration (Wright etal., 2015) and complex activity (Sandhir etal., 2012). Restoration of mitochondrial respiration has also been shown in rat models of traumatic brain injury as well as improvements in mitochondrial complex activity and mitochondrial glutathione (Patel etal., 2014). There is promising clinical evidence in support of adjunctive NAC in diverse psychiatric disorders (Deepmala etal., 2015). Asystematic review and meta-analysis has shown that overall, adjunctive NAC treatment seems beneficial for both unipolar and bipolar depression (Fernandes etal., 2016). To date, there have been 2 multi-site trials of NAC specifically exploring its use as an adjunctive treatment for BD. Several substudies have also been reported from these data. The initial study was conducted in participants with BD (n = 75) that were experiencing any symptoms (or euthymic). At 6months postbaseline, participants that received 2000 mg/d NAC (in addition to standard treatment) reported improved measures of BD symptoms, functioning, and quality of life. This improvement persisted up to 4 weeks following NAC treatment cessation. Adverse effects did not significantly differ between the NAC and placebo groups (Berk etal., 2008). Posthoc exploratory analyses were performed on a variety of data from this trial to assist in identifying who might benefit most from adjunctive NAC treatment in BD. This series of studies included the investigation of mania (or hypomania), bipolar II, major depressive episodes, cognition and comorbid systemic illness (Magalhães etal. 2011a, 2011b, 2013; Dean etal., 2012). When exploring major depressive episodes within the context of a BD sample, there were improvements following adjunctive Downloaded from https://academic.oup.com/ijnp/article/21/6/550/4955527 by guest on 11 November 2020
552 | International Journal of Neuropsychopharmacology, 2018 Table1. Summary of Clinical Evidence Studies Findings Conclusion Limitations NAC Berk etal., 2008a DBRPC of adjuntive treatment of depressive symptoms in 75 BD patients in maintenance phase with NAC (2g/d for 24 weeks+4-weeks washout) *PO: improvement on the MADRS sores 16.6 to 6.6 (week 24) Difference between placebo: -8.05 Benefits time-dependent Response NAC vs placebo: 50% reduction in total MADRS score: week 20 (46% vs 21%) week 24 (51% vs 18%) SO: Beneficial compared with placebo on symptoms, functioning, and quality of life NAC is an effective and safe adjunctive treatment for depressive symptoms in BD No effect on time to a mood episode (PO) Improvements in MADRS were lost after washout Berk etal., 2011 An 8-week open label phase of DBRPCT on efficacy of NAC (2g/d) as adjunctive treatment in BD on 149 patients with moderate depression *PO: reduction on BDRS score 19.7 to 11.1 after 8 weeks of treatment (P < .001) SO: reduction on MADRS scores, YMRS scores, SLICE-LIFE scores, CGI-BP (depression and overall) and improvements in GAF, SOFAS, Q-LES-Q Robust decrement in depression scores with NAC treatment No placebo group Inclusion of BD I, II & NOS Concomitant therapies Berk etal., 2012 A 24-week DBRPCT of adjunctive NAC treatment of maintenance phase of 149 BD patients who were previously screened for depression and received 2g/d NAC for 8 weeks and were randomized to maintain NAC adjunctive treatment or switch to placebo *PO: time to any intervention for mood symptoms was 199.9 d for the NAC group and 177.5 d for the placebo group 22 patients (37.3%) in the NAC group and 30 (48.4%) in the placebo group had a depressive episode, but the survival time for the NAC group was longer than for those in the placebo group (170.2 d vs 137.4 d) 7 patients (11.9%) in the NAC group and 2 (3.2%) in the placebo group had a manic episode during the maintenance phase phase (survival analysis was not conducted) 13 interventions for mood events in both groups SO: No significant alterations in clinical and functioning measures There were no significant differences between groups in recurrence or symptomatic outcomes The improvements in depressive symptoms reached a plateau in the openlabel phase and symptoms changed little from this very low base in randomized phase Absence of restrictions on cormobid diagnosis Concomitant therapies Sample size Length of the trial CoQ10 Foresteretal., 2012 An 8-week open label trial on CoQ10 (0.4-1.2g/d) effects on CK activity and mood (measured with PMRS and MADRS, respectively) as adjunctive treatment of 10 BD patients ≥55years old in depression phase+ 8 healthy controls *PO: Kfor of CK were 0.19 vs 0.2 as baseline in BD vs controls and 0.03 for BD and controls after 8 weeks SO: decrease in MADRS scores No significance difference between group in Kfor of CK Significant improvements in depression symptoms Sample size No placebo group Concomitant therapies Downloaded from https://academic.oup.com/ijnp/article/21/6/550/4955527 by guest on 11 November 2020
Pereira etal. | 553 Studies Findings Conclusion Limitations NAC ALA Brennan etal., 2013 A 12-week PCL of adjunctive treatment of 40 BD patients in depression phase with ALA (0.6– 1.8g/d) and ALC (1-3g/d) *PO: No significant changes were found between groups on MADRS scores In 20 patients (10 ALC/ALA and 10 placebo) phosphocreatine levels were measured by PMRS analyses: no differences found at baseline, no significant association between change in primary 31P-MRS measures and MADRS scores ALA and ALC did not show antidepressant effects or affect mitochondrial function Length of the trial Inclusion of BD I, II & NOS Concomitant therapies Low oral bioavailability of ALC and ALA SAMe Murphy etal., 2014 A 4-week DBRCT of adjunctive treatment with SAMe (1.6g/d) in 28 BD patients with depression episode (+2 weeks of no medications) *PO: no significant differences were observed in MADRS (0.04 vs 1), HAM-D (-0.56 vs 1)between SAMe and placebo group SO: no difference in YMRS (1.03 vs 0.32) No improvements in depressed patients beyond those observed in the placebotreated group Low oral bioavailability Lipinski etal., 1984 A 14-d open trial with SAMe (200mg/d i.v.) with 6 BD in depressive phase and 3 MDD 8 patients showed reduction in HAM-D scores ≥8 points (much improvement) 2 patients developed mania or hypomania Antidepressant effect Preliminary data CM Roitman etal., 2007 A 4-week open label trial with CM (3-5g/d) adjunctive treatment in 2 BD+8 MDD patients Improved HAM-D, CGI, and HAM-A scores for 8 MDD patients Switch to elevated mood in both BD patients Beneficial effect of creatine augmentation in unipolar depression, but possible precipitation of manic switch in bipolar depression Beneficial effect of creatine augmentation in unipolar depression, but possible precipitation of a manic switch in bipolar depression Beneficial effects on unipolar depression Possible manic switch in BD Preliminary data Small sample Melatonin Romo-Nava etal., 2014 An 8-week RDBPGPCCT of melatonin (5mg/d) adjunctive treatment (+2GAP) of 20 BD + 24 SZ *PO: melatonin group vs placebo: mean changes in DBP: 5.5mmHg vs 5.7mmHg; fat mass: 2.7 vs 0.2kg; triglycerides: 50.1 vs 20mg/dL (only in BD patients, not SZ) SO measures: Similar improvements in HAM-D and YMRS scores in the BD placebo and melatonin groups of BD placebo or melatonin groups Beneficial metabolic effect with melatonintreated patients suggests that melatonin may help to reestablish a damaged circadian rhythm in BD Table1. Continued Downloaded from https://academic.oup.com/ijnp/article/21/6/550/4955527 by guest on 11 November 2020
554 | International Journal of Neuropsychopharmacology, 2018 Studies Findings Conclusion Limitations NAC Bersani and Garavini, 2000 A 4-week open label trial of melatonin adjunctive treatment of 11 BD patients in manic phase with insomnia All patients had longer hours of sleep and severity of mania Significant decrease in BFRS scores Melatonin improved mania scale scores by the normalization of sleep/wake cycle Open study Small sample Measurement of sleep duration subjective—self-rating sleep questionnaire Pyrimidines Kondo etal., 2011 A 6-week open label trial of adjunctive treatment with uridine (1g/d) of 7 BD teenagers in depressive phase Improvement in the CDRS-R: 65.6 at baseline vs 27.2 after 6 weeks (54% reduction) Uridine was efficacious and well tolerated, showing a potential role in BD treatment Concomitant therapies Inclusion of BD I, II & NOS Jensen etal., 2008 A 6-week trial of adjunctive treatment of 11 BD patients with depression with TAU (18g/d) 6 patients responded to TAU, 5 did not TAU responders showed pH changes from baseline % changes and time effects of TAU on MADRS may indicate improvement in early symptoms TAU treatment may have clinical and biochemical effects—decrease symptoms of depression and improve mitochondrial functioning Small and heterogeneous population Gender disproportion No restrictions on medications Yoon etal., 2009 A 12-week DBRPCT of cytidine adjunctive treatment (with valproate) of 35 BD patients in depressive phase Improvement in depressive symptoms Reduction in cerebral glutamate/glutamine measured with PMRS Glutamate/glutamine alterations and reduction in depressive symptoms correlated in cytidine group and not in placebo group Cytidine augmentation of valproate associated with earlier response and reductions in cerebral glutamate/ glutamine levels Vitamin C Naylor and Smith, 1981 A 2-d RPT of treatment of 23 BD (11 manic and12 depressed) with 3g/d of vitamin C or placebo Lowest scores on the vitamin C-treated day were significantly lower (P < .005) than those on placebo-treated day (similar results even in patients divided into manic and depressed groups) Small sample Short period of time No controlgroup Kay etal., 1984 A 28-d DBPCT with 61 BD female patients: 29 manic (13 were medicated with 800g/d lithium and 16 received 4g vitamin C + 4g EDTA) 32 depressed (14 were medicated with 150mg amitriptiline and18 received 4g vitamin C+4g EDTA) Manic participants responded better to lithium than to vitamin C (43.3 vs 70.6) in the Beigel rating scale There was no significant difference in depression symptoms between amitriptyline or vitamin C in the depressed group on HAM-D (8.4 vs 10.7) and BDI (16.6 vs 19.8) ratings Vitamin C could be important in the co-treatment of bipolar depression, but the results do not support for mania Small sample Withdrawn patients Vitamin D Sikoglu etal., 2015 An 8-week open label trial of adjunctive treatment with vitamin D (2000 IU) of 16 BD patients (6-17 y old) in manic phase Decrease in YMRS scores Decrease in CDRS scores Significant increase in anterior cingulate cortex (ACC) glutamate, and γ-aminobutyric acid measured with PMRS 43% improvement in manic symptoms Open label Small sample Medication effects as a confounding factor Table1. Continued Downloaded from https://academic.oup.com/ijnp/article/21/6/550/4955527 by guest on 11 November 2020
Pereira etal. | 555 Studies Findings Conclusion Limitations NAC Vitamin B9 (folic acid) Behzadi etal., 2009 A 3-week DBPRCT of adjunctive treatment of folic acid (+valproate) of 88 BD manic patients Statistically significant difference in YMRS scores between BD group and control groups (7.1 ± 0.9 vs 10.1 ± 1.1) Folic acid use as augmentation to valproate showed better response in BD patients in treatment of acute mania Short follow-up Coppen etal., 1986 A 52-week DBPRCT of adjunctive treatment of 200μg folic acid (+lithium) of 75 BD (n = 17), MDD, and schizoaffective patients 21 patients with plasma folate concentration ≤12.9ng/mL had a higher Beck score (6.6 + 1.7) than the 18 patients with plasma folate concentration >13.0ng/mL (3.5 + 0.8) Lower plasma folate concentrations can be correlated with higher affective morbidity Daily supplement of folic acid could be helpful in long-term lithium prophylaxis Nierenberg etal., 2017 A 6-week open label of adjunctive treatment with L-methylfolate (15mg/d) of 10 BD patients in depressive phase 55% improvement in depression symptom in MADRS and small mean decrease in YMRS Potential as BD adjunctive treatment Choline Stoll etal., 1996 Collection of 6 case reports of choline augmentation of lithium in rapidcycling BD patients 5 patients had reduction of manic symptoms 2 patients had improvement on depressive symptoms Choline responders exhibited a basal ganglia rise in concentration of choline-containing compounds Choline was well tolerated in all cases and in combination with lithium could be an effective therapy Lyoo etal., 2003b A 12-week DBT of adjunctive treatment of choline (+lithium) of 8 rapid-cycling BD patients No significant differences in change-frombaseline measures of CGI, YMRS, or HAM-D Choline-treated group showed decreased brain purine levels compared with placebo Adjuvant treatment with choline resulted in lower purine levels and increased membrane phospholipid synthesis Abbreviations: ALA, α-lipoic acid; ALC, acetyl-L-carnitine; BDI, Beck Depression Inventory; BD, bipolar disorder; BDRS, Bipolar Depression Rating Scale; BPRS, Brief Psychiatric Rating Scale; CDRS-R, Children’s Depression Rating Scale-Revised; CGI-BP, Clinical Global Impressions-Bipolar Disorder; CK, creatine kinase; CoQ10, coenzyme Q10; CM, creatine monohydrate; DBP, diastolic blood pressure; DBRPCT, double-blind randomized placebo-controlled trial; EDTA, ethylene diamine tetra acetic acid; GAF, Global Assessment of Functioning; 2GAP, second generation antipsychotics; HAM-A, Hamilton Anxiety Rating Scale; HAM-D, Hamilton Rating Scale for Depression; Kfor, forward rate constant; MADRS, Montgomery–Åsberg Depression Rating Scale; MDD, major depression disorder; NAC, N-acetyl cysteine; NOS, not otherwise especified; PCL, placebo control trial; PMRS, phosphorus magnetic resonance spectroscopy; PMRS, proton magnetic resonance spectroscopy; PO, primary outcomes; Q-LES-Q, Quality of Life Enjoyment and Satisfaction Questionnaire; RDBPGPCCT, randomized, double-blind, parallel-group, placebo-controlled clinical trial; SAMe, S-adenosylmethionine; SLICE-LIFE, Streamed Longitudinal Interval Clinical Evaluation for the Longitudinal Interview Follow-Up Evaluation; SO, secondary outcomes; SOFAS, Social and Occupational Assessment Scale; SZ, schizophrenia; TAU, triacetyluridine; YMRS, Young Mania Rating Scale. Table1. Continued Downloaded from https://academic.oup.com/ijnp/article/21/6/550/4955527 by guest on 11 November 2020
556 | International Journal of Neuropsychopharmacology, 2018 NAC compared with placebo (Magalhães et al., 2011b). The investigation of those experiencing mania indicated withingroup improvements in the NAC group (Magalhães etal., 2013). Similarly, when exploring a subgroup of participants (n = 14) with bipolar II (divided in 2 groups of 7 patients each randomized to placebo or NAC), NAC was found to improve symptoms in 6/7 participants, compared with 2/7 in the placebo group (Magalhães etal., 2011a). NAC was also shown to improve functional outcomes for people experiencing cardiovascular or endocrine comorbidities when compared to those who did not (Magalhães etal., 2012). Finally, a paper on posthoc analyses has reported no change in cognition in a small subset of participants following NAC (Dean etal., 2012). The next study included a maintenance design with an initial open-label phase. Participants were given 2000mg/d of NAC (n = 149) for a total of 8 weeks and were then randomized to continuation of adjunctive NAC treatment or a placebo. The openlabel phase showed significant improvements in participants experiencing bipolar depression (Berk etal., 2011). However, in the maintenance (randomized) phase, participants in both arms generally stayed well, which resulted in no significant treatment effects (Berk etal., 2012). We further searched ANZCTR and Clinicaltrials.gov to ascertain if there are upcoming studies in this area. Aprotocol has been published describing a study of NAC and a combination of other agents that enhance mitochondrial function, compared with placebo, over 16 weeks of treatment (Dean etal., 2015). Overall, NAC is a potentially useful adjunctive therapy for BD and, in particular, bipolar depression during the acute phase. NAC has been shown to enhance mitochondrial function in preclinical models. However, no clinical studies that have investigated NAC for BD have evaluated outcomes related to mitochondrial function. Further research is required to explore the interactions of NAC clinical efficacy and changes in relevant pathways, including pathways relevant to mitochondrial function. CoenzymeQ10 Coenzyme Q10 (CoQ10), also known as ubiquinone, is a powerful lipid-soluble antioxidant that reduces the flow of electrons on the ROS-producing regions of Complex I, II, and III of the mitochondria (Lenaz etal., 2002; Nierenberg etal., 2013). CoQ10 reduces ROS by neutralizing the free radical alpha-tocopheroxyl to alpha-tocopherol (vitamin E) and plays a role in the biosynthesis of adenosine triphosphate (ATP) (Morris etal., 2013; Nierenberg etal., 2013). The genes associated with these complexes and the transportation of electrons across them are expressed differently in BD compared with healthy controls (Sun etal., 2006b). Supplementary CoQ10 has poor oral bioavailability; however, it does cross the blood-brain barrier (Matthews etal., 1998). Morris etal. (2013) discussed the reduction in CoQ10 levels in psychiatric and mitochondrial disorders such as depression, chronic fatigue syndrome, fibromyalgia, and Parkinson’s disease and postulated that CoQ10 supplementation could be a treatment for these disorders. However, a meta-analysis of CoQ10 supplementation compared with placebo showed no significant benefits for participants with Parkinson’s disease (Negida etal., 2016). There have been several studies proposing the use of CoQ10 supplementation as a mitochondrial enhancing agent in general and for BD in particular (Morris et al., 2013; Nierenberg etal., 2013). Despite this, there have been only 2 studies directly looking at CoQ10 supplementation and BD. One study explored CoQ10 in combination with other mitochondrial agents (such as NAC and b-group vitamins) as an adjunctive treatment for bipolar depression (Dean etal., 2015). This study has been completed but results are still pending. Forester etal. (2012) investigated an 8-week intervention of CoQ10 in a sample of 10 outpatients aged 55years and older with a DSM-IV diagnosis of bipolar depression in an 8-week study. Participants were administered CoQ10 and compared with 8 healthy controls who did not receive CoQ10 supplementation. The maximum dose of CoQ10 was 1200mg/d, starting at 400mg/d and titrated up by 400mg/d every 2 weeks. Participants on CoQ10 showed modest but significant improvements in their depression symptoms (measured on the Montgomery– Åsberg Depression Rating Scale MADRS) over the 8-week study. Furthermore, this study also investigated mitochondrial function via phosphorus magnetic resonance spectroscopy and reported no significant differences between groups for creatine kinase (a mitochondrial protein). This small study is limited by the sample size and lack of placebo control but highlights the potential of CoQ10 as an antidepressant and treatment for BD. Alpha-LipoicAcid Alpha-lipoic acid (ALA), also known as thioctic acid, is a pleiotropic substance (Gomes and Negrato, 2014). ALA is a strong antioxidant (Suzuki etal., 1991; Moini etal., 2002). It increases levels of glutathione (Han et al., 1997; Yamada et al., 2011; Kleinkauf-Rocha etal., 2013), raises hepatocyte ascorbate levels (Lykkesfeldt etal., 1998; Michels etal., 2003), downregulates nuclear factor kappa-light-chain-enhancer of activated B cells (DeMarco etal., 2004), and is a metal chelator (Ou etal., 1995; Suh etal., 2005), an antiviral in glial cells (Scumpia etal., 2014), and a glucose uptake promoter (Estrada etal., 1996; Henriksen etal., 1997; Saengsirisuwan etal., 2004), increasing GLUT4 levels and insulin action (Hughes etal., 1993). Relevant to the current review, ALA also has a role as a mitochondrial agent. It can be endogenously synthesized in the mitochondria where it acts as a coenzyme for the formation of pyruvate dehydrogenase and α-ketoglutarate—both essential components of the Krebs cycle. Because pyruvate dehydrogenase converts pyruvate to acetyl CoA, ALA decreases lactate levels, thus inhibiting glycolysis (Gomes and Negrato, 2014). It also modulates the key regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PPAR-GC-1α) (Liu, 2008). PPAR-GC-1α stimulation has been linked to neuroprotection and its suppression to mitochondrial dysfunction and neurodegeneration (Cui etal., 2006; St-Pierre etal., 2006). ALA also affects the mitochondrial pathway of apoptosis, prompting research in oncology as an agent with antimetastatic potential (Dörsam and Fahrer, 2016). This provides a rationale for its action in mood and cognitive disorders. In a corticosterone-induced model of depression in mice, ALA showed antidepressant properties and reversed brain-derived neurotrophic factor reduction in the hippocampus and striatum (deSousa etal., 2015). In a d-amphetamine-induced model of mania, ALA was able to both prevent and reverse symptoms with comparable efficiency to lithium (Macêdo etal., 2012). Only one clinical trial has explored ALA as an adjunctive treatment for bipolar depression. The trial tested a combination of ALA (600–1800mg/d) and acetyl-L-carnitine (ALC) (1000– 3000mg/d) or placebo for 12 weeks in 40 participants with bipolar depression. Previous treatment (stable for at least 4 weeks) was continued. The primary outcome was depression, measured on Downloaded from https://academic.oup.com/ijnp/article/21/6/550/4955527 by guest on 11 November 2020
Pereira etal. | 557 the MADRS. No significant changes were found between groups (Brennan etal., 2013). As the authors note, the shorter duration of the study (12 weeks) compared with a positive RCT of a mitochondrial agent (NAC) in BD (24 weeks) (Berk etal., 2008), the inclusion of bipolar Iand II types, concomitant medication use, and possible low oral bioavailability of the agents are all potential confounders that should be addressed. More research is required to determine the efficacy of ALA in BD. Moreover, there is one study (described earlier) in bipolar depression that is currently being completed that includes a combination of agents including ALA, ALC, and NAC (ACTRN12612000830897). ALC In addition to the role of ALC in mitochondrial β-oxidation and energy production (Hoppel, 2003), ALC has antioxidant properties (Gülçin, 2006; Mescka etal., 2011). Additionally, ALC has been proposed to mediate the transfer of acetyl groups for acetylcholine synthesis, modulate nerve growth factors and gene expression (Nałecz and Nałecz, 1996; Binienda, 2003; Nacz etal., 2004), and counter glutamate-induced excitotoxicity (Zanelli etal., 2005). Data from animal models provide further evidence for ALC’s therapeutic potential due to its role as an antioxidant and in improving mitochondrial energy production (Rao et al., 1997; Aureli etal., 1998; Hagen etal., 2002b; Al-Majed etal., 2006), its neuroprotective action in trauma (Karalija etal., 2014) and ischemia (Rosenthal etal., 1992; Barhwal etal., 2007), its antidepressant effect in the forced swim test (FST) (Wang etal., 2015), and its ability to reverse memory loss in older rats (Liu etal., 2002). Two patients with geriatric depression treated with ALC showed increases in PCr and β-nucleoside triphosphate (β-NTP) levels (Pettegrew etal., 2002). PCr serves as a reservoir for highenergy phosphates, and β-NTP is acknowledged as an index of brain levels of ATP. Thus, these results provide support for a link between the antidepressant action of ALC and improved energy production within thebrain. However, the only RCT in BD reported no effect when administered in combination with ALA (Brennan et al., 2013) (see above). Furthermore, the change in PCr and β-NTP, previously found in geriatric depression patients (Pettegrew etal., 2002), was not observed (Brennan etal., 2013). Two case reports of ALCassociated relapse in BD also suggest some caution with clinical use. The first case-reports detail a psychotic episode in a known BD type Ipatient, 5days after starting treatment with nutritional supplements including vitamin C, vitamin E, and ALC (500mg/d) (Evcimen etal., 2007). Manic symptoms associated with self-prescribed ALC treatment (2000mg/d) in a man with BD type Iresolved 3days after cessation of ALC (Goodison etal., 2016). S-Adenosylmethionine S-Adenosylmethionine (SAMe) results from the combination of ATP and methionine and plays a crucial role as a methyl donor in reactions involving methyltrasnferases (Bottiglieri, 2002). SAMe is also a precursor molecule for glutathione production, which plays an essential role in reducing oxidative stress. In the brain, SAMe repairs and degrades proteins and activates thyroxine hydroxylase through methylation, which is critical in the synthesis and regulation of monoamines (i.e., dopamine, serotonin), which are known to be dysregulated in BD (Bottiglieri etal., 2000, 2002). Recently, an RCT of SAMe as an addon to an approved mood stabilizer in 20 participants with BD (type Iand II) was conducted. To enroll, subjects were required to have not responded previously to either 2 antidepressants (of different classes) or to 2 different mood stabilizers. No significant differences were observed in MADRS, Hamilton Rating Scale for Depression (HAM-D), or Young Mania Rating Scale (YMRS) between the SAMe and placebo groups. No switches to mania were reported (Murphy etal., 2014). Carney etal. (1989) reported 3 open label trials and 1 placebo-controlled trial after a drugfree period of at least 7days. There were 14 unipolar depression and 11 BD participants. Nine of the 11 BD participants switched to hypomania, mania, or “elevated mood.” The other 2 participants did not respond to treatment (Carney etal., 1989). In an open-label trial of i.v. SAMe monotherapy for depression, 7 of 9 patients improved or had depression remission. There were 2 case reports of mood switch in BD patients, 1 of mania, and 1 of hypomania (Lipinski etal., 1984). Due to the potential for manic switching, SAMe for BD should be investigated with caution. In unipolar depression, a meta-analysis in 2002 showed that SAMe is superior to placebo improving HAM-D scores (Hardy et al., 2003). Arecent systematic review collected clinical information from 115 clinical trials and 17 preclinical studies on the effect of SAMe on several neuropsychiatric conditions. Positive but limited evidence was found for the use of SAMe in major depressive disorder (MDD) as both a monotherapy and adjunctive therapy (Sharma et al., 2017). Recently, 2 studies have demonstrated benefits of SAMe as an augmentation antidepressant therapy. In a 6-week, double blind, placebo RCT with serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors nonresponders, participants undergoing SAMe augmentation had lower HAM-D score and higher remission rates (final HAM-D score<8) than placebo (Papakostas etal., 2010). Creatine Monohydrate Creatine is the precursor of PCr. Long-term decrease of PCr decreases ATP production, attributable to mitochondrial dysfunction (Erecińska and Silver, 1989). Oral supplementation of creatine monohydrate increases creatine and brain concentrations of PCr (Dechent etal., 1999; Lyoo etal., 2003a). In BD, decreased PCr concentrations have been reported (Stork and Renshaw, 2005). Furthermore, creatine has been shown to have antioxidant properties in animal models of oxidative stress (Sullivan etal., 2000; Tarnopolsky and Beal, 2001; Lawler etal., 2002) A 4-week open-label trial with 10 participants experiencing treatment-resistant depression (8 unipolar and 2 bipolar) showed improved depression scores with 3 to 5 g/d creatine monohydrate augmentation, provoking switch to elevated mood in both BD patients (Roitman etal., 2007). Two trials focusing on a combination of cytidine and creatine in bipolar depression are currently being conducted (NCT01543139; NCT02625779). A 6-week, double blind, placebo RCT to evaluate the efficacy of creatine monohydrate as an adjunctive therapy for BD type Idepression (NCT01655030) is also currently recruiting. Melatonin Melatonin regulates several homeostatic processes such as circadian rhythm maintenance, growth hormone stimulation, and insulin secretion (Paredes etal., 2014; Simões etal., 2016; Zhang et al., 2016). Relevant to mitochondrial physiology, melatonin improves oxidative phosphorylation, increasing the activity of the Iand IV dose-dependent complexes and membrane fluidity and closes the mitochondrial permeability transition pore Downloaded from https://academic.oup.com/ijnp/article/21/6/550/4955527 by guest on 11 November 2020
558 | International Journal of Neuropsychopharmacology, 2018 (a protein complex spanning the inner and outer mitochondrial membranes), preventing ATP depletion and necrotic cell death (Acuña-Castroviejo etal., 2001, 2007; Martín etal., 2002; Leon etal., 2005). Moreover, melatonin and some of its metabolites play an important antiinflammatory and antioxidant role through scavenging oxygen and nitrogen-based ROS (LópezBurillo et al., 2003; Korkmaz et al., 2009). Melatonin directly boosts mRNA expression of genes implicated in the production of glutathione peroxidase and superoxide dismutase, 2 antioxidant enzymes (Rodriguez etal., 2004; Acuña-Castroviejo etal., 2007; Anderson and Maes, 2014). Furthermore, peripheral melatonin, produced outside the brain, is decreased in BD compared with healthy controls, suggesting supplemental melatonin may be a relevant intervention in this population (Anderson and Maes, 2014). In an 8-week, double blind, placebo control trial, 44 participants (24 participants with SZ and 20 with BD) treated with second-generation antipsychotics received low dosages of melatonin (5mg/d) and placebo. The melatonin group showed lower diastolic blood pressure and less weight gain, these results being greater in the BD group (Romo-Nava etal., 2014). In an openlabel trial, melatonin improved mania scale scores and sleeping patterns (Bersani and Garavini, 2000) but had no significant effects on mood or sleep in a double-blind, placebo-controlled trial using the same dose with 5 rapid-cycling DSM-III-R BD patients (Leibenluft etal., 1997). McElroy et al. (2011) tested ramelteon (a highly selective melatonin MT1/MT2 receptor agonist) as an adjunctive treatment in 21 outpatients with bipolar I disorder with mild-tomoderate manic symptoms and sleep disturbance in an 8-week, double-blind, fixed-dose (8mg/d) study. Aglobal improvement in a global rating of depressive symptoms was reported; however, no significant differences in ratings of insomnia, mania, and global severity of illness were observed. Norris etal. (2013) conducted a double-blind, randomized, placebo-controlled trial of adjunctive ramelteon in euthymic bipolar patients with sleep disturbances and reported that participants receiving ramelteon were significantly less likely to relapse compared with placebo. Recently, a RCT comparing placebo with sublingual ramelteon in different dosages (0.1mg, 0.4mg, 0.8mg, once daily) as adjunctive maintenance therapy in stable BD patients did not show significant differences between any dose of ramelteon and placebo (Mahableshwarkar etal., 2017). The study was terminated before the expected sample size due to meeting the futility criteria. All studies showed ramelteon was well tolerated and associated with no serious adverse events. Agomelatine (an agonist of melatonin 1 and 2 receptors and antagonist of serotonin 2C receptors drug) has also been investigated as an adjunctive treatment for bipolar depression. In an open-label trial with 21 type IBD patients in a severe depressive episode (14 treated with lithium and 7 with valpromide), agomelatine was added at 25mg/d for at least 6 weeks and, if participants opted-in, up to 1year. At week 6, 81% of patients improved >50% in HAM-D score from baseline and almost 50% in the first study week. Three patients switched to mania or hypomania from the sixth week until the complete year follow-up (Calabrese etal., 2007). In a similar study, 28 type II BD patients in a severe depressive episode (11 treated with lithium and 17 with valproate) were treated with agomelatine at fixed dosages of 25mg/d from at least 6 weeks to a possible 30-week extension. At 6 weeks, 64% of patients improved >50% in HAM-D score from baseline and 86% responded at 36 weeks. There were 4 drop-outs in total due to polarity change (1 manic and 3 hypomanic episodes) (Fornaro etal., 2013). Recently, 344 type IBD patients undergoing a current major depressive episode that were treated with lithium or valproic acid for at least 6 weeks were randomized to treatment with agomelatine or placebo (n = 172 each group) in a double-blind study (Yatham etal., 2016). No significant differences between both groups in MADRS total score or response or remission rates from baseline to endpoint were found. The number of manic or hypomanic symptoms was comparable between both groups at each assessment time. As a number of sites had placebo response rates of 100%, when these were excluded in a posthoc analysis, a signal favoring agomelatine over placebo emerged. While the meta-analyses in unipolar depression confirm the antidepressant effects of agomelatine (Singh etal., 2012; Taylor etal., 2014), melatonin supplementation did not significantly improve treatment or prophylaxis of unipolar depression (Hansen etal., 2014). Pyrimidines The pyrimidine nucleosides such as uridine, triacetyluridine, and cytidine have effects on mitochondrial function, glutamatergic transmission, catecholamine synthesis, and cerebral phospholipid metabolism, which has been linked to the pathophysiology of BD (Yoon etal., 2009; Kondo etal., 2011). Uridine (1000mg/d) was studied in a 6 weeks open-label trial of 7 teenagers with bipolar depression. Children’s Depression Rating Scale-Revised and the Clinical Global Impressions scale were used to measure the treatment results. Uridine was well tolerated and depressive symptoms decreased (Kondo etal., 2011). In another 6-week study (n = 20), 18g/d day of triacetyluridine (TAU), a uridine prodrug, or placebo was given to patients with bipolar depression. BD patients who had a reduction in MADRS scores ≥50% showed a greater difference in pH changes (assessed by phosphorus magnetic resonance spectroscopic imaging (PMRSI)) compared with TAU nonresponders, suggesting that TAU treatment can have benefits in depressive symptoms and in mitochondrial function (Jensen etal., 2008). Cytidine, available from dietary sources and converted in uridine in the human body, was investigated in a 12-week, randomized, placebo trial with 35 patients with bipolar depression. Participants were randomly given valproate plus placebo or valproate plus cytidine. At 2, 4, and 12 weeks, the cerebral levels of glutamate/glutamine were measured using PMRSI. The results showed that cytidine supplementation resulted in earlier improvement in symptoms of depression and greater reduction in glutamate/glutamine levels. These data suggest that the observed therapeutic effect of cytidine may be mediated via a decrease in cerebral glutamate/ glutamine levels (Yoon etal., 2009). Choline Choline is a constituent of the neurotransmitter acetylcholine, a major methyl-donor, and needed for structural integrity and intracellular signaling within cell membranes. In an open-label trial, Stoll etal. (1996) studied the effects of lithium augmentation with choline in 6 rapid-cycling BD outpatients. Five participants experienced a reduction in manic symptoms and 4 had a reduction in all mood symptoms during choline therapy. The impact on depression was variable. Lyoo etal. (2003b) studied 8 lithium-treated, rapid-cycling BD Iand II patients randomized to receive either choline or placebo, and reported significantly decreased brain purine levels, a marker of energy metabolism. VitaminA Both deficient and excessive levels of vitamin Adisrupt many human systems, including the central nervous system (CNS) Downloaded from https://academic.oup.com/ijnp/article/21/6/550/4955527 by guest on 11 November 2020
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