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. Significance Statement Box Sample Keywords: adjunctive, bipolar disorder, complimentary therapies, mitochondria 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. 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, 550 provided the original work is properly cited. For commercial re-use, please contact firstname.lastname@example.org Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/550/4955527 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Pereira et al. | 551 Some already approved drugs for BD treatment affect mito- Introduction chondrial function. Lithium and valproic acid may induce Bipolar disorder (BD) is a complex illness with an approximate selective complex III and V phosphorylation and increase prevalence of 1% (Ferrari et al., 2016). It can cause marked dis- energy production (Corena-McLeod et al., 2013). Lithium treat- ability and social impairment, particularly among people who ment increased electron transport chain complex I expression experience continued subthreshold symptoms between acute and activity in postmortem brain studies (Sun et al., 2006a). phases, with depression being the greatest contributor (Judd Lithium has also been robustly associated with lower oxidative et al., 2008). stress levels (Khairova et al., 2011; Banerjee et al., 2012; de Sousa Current pharmacological treatment offers limited efficacy et al., 2014) and a reversal of mitochondrial calcium alterations overall, either in preventing relapses or recovery from acute (Machado-Vieira et al., 2011). Atypical antipsychotics increase episodes of depression (Perlis et al., 2006). The current treat- superoxide dismutase gene expression and have antiapoptotic ment for the maintenance phase is mood stabilizers (Chen properties (He et al., 2009). et al., 1999; Machado-Vieira et al., 2009; Oikawa and Sng, 2016). As our understanding of the pathophysiology of BD increases, Antipsychotics and antidepressants are prescribed both in acute new compounds targeting mitochondrial function are of inter- phases and maintenance phases, especially when subthreshold est. The aim of this review is to give an update on potential symptoms remain. While antipsychotics and mood stabilizers interventions for BD that act via modulation of mitochondrial tend to effectively treat mania (Perlis et al., 2006), the treatment function (see Table 1). Where available, data from randomized of bipolar depression is more challenging, as these agents may controlled trials were preferred. However, where no clinical data not improve depressive symptoms (Calabrese et al., 2007; Sachs exist, data from case reports or open-label studies were also et al., 2007), and treatment with antidepressants may induce discussed. phase switching, particularly with monotherapy (Post et al., 2006; Viktorin et al., 2014). An additional limitation to effec- Mitochodrial Agents tive treatment options is the current lack of understanding of the underlying pathophysiology of bipolar depression (Sigitova N-Acetyl Cysteine et al., 2017). Therefore, several new biological hypotheses are emerging, including neuro-inflammation (Naaldijk et al., 2016), N-acetyl cysteine (NAC) is increasingly being used as an adjunc- neurodegeneration (Myint and Kim, 2014), and, relevant to the tive therapy in psychiatry (Berk et al., 2013). Its use across psy- current review, mitochondrial dysfunction (Kato and Kato, 2000; chiatric disorders is due to the number of mechanisms of action Kato, 2007, 2010). relevant to mental illness. In addition to providing rate-limiting Different lines of evidence implicate mitochondrial impair - cysteine for glutathione production, NAC has also been shown to ment in BD. A higher prevalence of mood disorders is reported be an antiinflammatory, enhance neurogenesis, decrease apop- in people with mitochondrial diseases compared to the gen- tosis, modulate glutamate pathways, and, importantly, alter eral population (Fattal et al., 2007). Furthermore, morphological mitochondrial activity (Samuni et al., 2013). In both mouse (R6/1) abnormalities and marginal distribution of mitochondria were and rat (3-nitropropionic acid) models of Huntington’s Disease, reported both in postmortem prefrontal cortex samples and NAC has been shown to restore mitochondrial respiration peripheral cells from living BD patients. These findings were (Wright et al., 2015) and complex activity (Sandhir et al., 2012). controlled for lithium treatment (Cataldo et al., 2010). A plethora Restoration of mitochondrial respiration has also been shown in of molecular data also confirms abnormal energy metabolism rat models of traumatic brain injury as well as improvements in in BD. Indeed, postmortem studies have reported higher lactate mitochondrial complex activity and mitochondrial glutathione concentrations in the brain of people with BD, which suggests a (Patel et al., 2014). shift from oxidative phosphorylation to glycolysis (Dager et al., There is promising clinical evidence in support of adjunc- 2004). This observation has been supported by similar studies tive NAC in diverse psychiatric disorders (Deepmala et al., 2015). using magnetic resonance spectroscopy (Stork and Renshaw, A systematic review and meta-analysis has shown that overall, 2005) and cerebrospinal fluid studies (Regenold et al., 2009). adjunctive NAC treatment seems beneficial for both unipolar Val66met, a brain-derived neurotrophic factor polymorphism and bipolar depression (Fernandes et al., 2016). that has been associated with BD, results in lower prefrontal To date, there have been 2 multi-site trials of NAC specifi- cortex phosphocreatine (PCr) and creatine levels in BD patients cally exploring its use as an adjunctive treatment for BD. Several (Frey et al., 2007). substudies have also been reported from these data. The initial Electron transport chain complex I is decreased in both lev- study was conducted in participants with BD (n = 75) that were els and activity in BD patients (Andreazza et al., 2010). Moreover, experiencing any symptoms (or euthymic). At 6 months post- BD patients downregulate nuclear transcripts for proteins of baseline, participants that received 2000 mg/d NAC (in addi- the entire electron transport chain when subject to glucose tion to standard treatment) reported improved measures of BD deprivation, while controls seem to have the opposite response symptoms, functioning, and quality of life. This improvement (Naydenov et al., 2007). There is also robust evidence of increased persisted up to 4 weeks following NAC treatment cessation. lipid peroxidation and alterations in calcium metabolism in BD Adverse effects did not significantly differ between the NAC and (Munakata et al., 2004; Kato, 2008). A decrease in the expres- placebo groups (Berk et al., 2008). sion of genes regulating oxidative phosphorylation and pro- Posthoc exploratory analyses were performed on a variety of teasome degradation in BD patients in comparison to patients data from this trial to assist in identifying who might benefit with schizophrenia (SZ) and healthy controls was also shown most from adjunctive NAC treatment in BD. This series of stud- ies included the investigation of mania (or hypomania), bipolar (Konradi et al., 2004). High energy requirements in the brain may also increase the production of reactive oxygen species (ROS), II, major depressive episodes, cognition and comorbid systemic illness (Magalhães et al. 2011a, 2011b, 2013; Dean et al., 2012). potentially damaging mitochondria themselves, resulting in an exacerbation of mitochondrial energy production failure (Hagen When exploring major depressive episodes within the context of a BD sample, there were improvements following adjunctive et al., 2002a). Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/550/4955527 by Ed 'DeepDyve' Gillespie user on 21 June 2018 552 | International Journal of Neuropsychopharmacology, 2018 Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/550/4955527 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Table 1. Summary of Clinical Evidence Studies Findings Conclusion Limitations NAC Berk et al., 2008a DBRPC of adjuntive treatment *PO: improvement on the MADRS sores 16.6 to NAC is an effective and safe adjunctive No effect on time to a mood of depressive symptoms in 75 6.6 (week 24) treatment for depressive symptoms in episode (PO) BD patients in maintenance Difference between placebo: -8.05 BD Improvements in MADRS were phase with NAC (2 g/d for 24 Benefits time-dependent lost after washout weeks + 4-weeks washout) 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 Berk et al., 2011 An 8-week open label phase of *PO: reduction on BDRS score 19.7 to 11.1 after Robust decrement in depression scores No placebo group DBRPCT on efficacy of NAC (2 g/d) 8 weeks of treatment (P < .001) with NAC treatment Inclusion of BD I, II & NOS as adjunctive treatment in BD SO: reduction on MADRS scores, YMRS scores, Concomitant therapies on 149 patients with moderate SLICE-LIFE scores, CGI-BP (depression and depression overall) and improvements in GAF, SOFAS, Q-LES-Q Berk et al., 2012 A 24-week DBRPCT of adjunctive *PO: time to any There were no significant differences Absence of restrictions on NAC treatment of maintenance intervention for mood symptoms was 199.9 between groups in recurrence or cormobid diagnosis phase of 149 BD patients who were d for the NAC group and 177.5 d for the symptomatic outcomes Concomitant therapies previously screened for placebo group The improvements in depressive Sample size depression and received 2 g/d NAC symptoms reached a plateau in the open- Length of the trial for 8 weeks and were randomized 22 patients (37.3%) in the NAC group and 30 label phase and symptoms changed little to maintain NAC adjunctive (48.4%) in the placebo group had a depressive from this very low base in randomized treatment or switch to placebo episode, but the survival time for the NAC phase 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 CoQ10 Forester et al., 2012 An 8-week open label trial on *PO: Kfor of CK were 0.19 vs 0.2 as baseline in No significance difference between group Sample size CoQ10 (0.4-1.2 g/d) effects on CK BD vs controls and 0.03 for BD and controls in Kfor of CK No placebo group activity and mood (measured with after 8 weeks Significant improvements in depression Concomitant therapies PMRS and MADRS, respectively) SO: decrease in MADRS scores symptoms as adjunctive treatment of 10 BD patients ≥55 years old in depression phase + 8 healthy controls Pereira et al. | 553 fi fi Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/550/4955527 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Table 1. Continued Studies Findings Conclusion Limitations NAC ALA Brennan et al., 2013 A 12-week PCL of adjunctive *PO: No significant changes were found ALA and ALC did not show antidepressant Length of the trial treatment of 40 BD patients in between groups on MADRS scores effects or affect mitochondrial function Inclusion of BD I, II & NOS depression phase with ALA (0.6– In 20 patients (10 ALC/ALA and 10 placebo) Concomitant therapies 1.8 g/d) and ALC (1-3 g/d) phosphocreatine levels were measured by Low oral bioavailability of ALC PMRS analyses: no differences found at and ALA baseline, no significant association between change in primary P-MRS measures and MADRS scores SAMe Murphy et al., A 4-week DBRCT of adjunctive *PO: no significant differences were observed No improvements in depressed patients Low oral bioavailability 2014 treatment with SAMe (1.6 g/d) in in MADRS (0.04 vs 1), HAM-D (-0.56 vs beyond those observed in the placebo- 28 BD patients with depression 1) between SAMe and placebo group treated group episode (+2 weeks of no SO: no difference in YMRS (1.03 vs 0.32) medications) Lipinski et al., 1984 A 14-d open trial with SAMe 8 patients showed reduction in HAM-D scores Antidepressant effect Preliminary data (200 mg/d i.v.) with 6 BD in ≥8 points (much improvement) depressive phase and 3 MDD 2 patients developed mania or hypomania CM Roitman et al., 2007 A 4-week open label trial with CM Improved HAM-D, CGI, and HAM-A scores for 8 Benecial eﬀect of creatine augmentation Preliminary data (3-5 g/d) adjunctive treatment in 2 MDD patients in unipolar depression, but possible Small sample BD + 8 MDD patients Switch to elevated mood in both BD patients precipitation of manic switch in bipolar depression Benecial 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 Melatonin Romo-Nava et al., 2014 An 8-week RDBPGPCCT of melatonin *PO: melatonin group vs placebo: mean Beneficial metabolic effect with melatonin- (5 mg/d) adjunctive treatment changes in DBP: 5.5 mmHg vs 5.7 mmHg; treated patients suggests that melatonin (+2GAP) of 20 BD + 24 SZ fat mass: 2.7 vs 0.2 kg; triglycerides: 50.1 vs may help to reestablish a damaged 20 mg/dL (only in BD patients, not SZ) circadian rhythm in BD SO measures: Similar improvements in HAM-D and YMRS scores in the BD placebo and melatonin groups of BD placebo or melatonin groups 554 | International Journal of Neuropsychopharmacology, 2018 Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/550/4955527 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Table 1. Continued Studies Findings Conclusion Limitations NAC Bersani and Garavini, A 4-week open label trial of All patients had longer hours of sleep and Melatonin improved mania scale scores by Open study 2000 melatonin adjunctive treatment severity of mania Significant decrease in the normalization of sleep/wake cycle Small sample of 11 BD patients in manic phase BFRS scores Measurement of sleep duration with insomnia subjective—self-rating sleep questionnaire Pyrimidines Kondo et al., 2011 A 6-week open label trial of Improvement in the CDRS-R: 65.6 at baseline vs Uridine was efficacious and well tolerated, Concomitant therapies adjunctive treatment with uridine 27.2 after 6 weeks (54% reduction) showing a potential role in BD treatment Inclusion of BD I, II & NOS (1 g/d) of 7 BD teenagers in depressive phase Jensen et al., 2008 A 6-week trial of adjunctive 6 patients responded to TAU, 5 did not TAU treatment may have clinical Small and heterogeneous treatment of 11 BD patients with TAU responders showed pH changes from and biochemical effects—decrease population depression with TAU (18 g/d) baseline symptoms of depression and improve Gender disproportion % changes and time effects of TAU on mitochondrial functioning No restrictions on medications MADRS may indicate improvement in early symptoms Yoon et al., 2009 A 12-week DBRPCT of cytidine Improvement in depressive symptoms Cytidine augmentation of adjunctive treatment (with Reduction in cerebral glutamate/glutamine valproate associated with earlier response valproate) of 35 BD patients in measured with PMRS and reductions in cerebral glutamate/ depressive phase Glutamate/glutamine alterations and reduction glutamine levels in depressive symptoms correlated in cytidine group and not in placebo group Vitamin C Naylor and Smith, 1981 A 2-d RPT of treatment of 23 BD (11 Lowest scores on the vitamin C-treated day Small sample manic and 12 depressed) with were significantly lower (P < .005) than those Short period of time 3 g/d of vitamin C or placebo on placebo-treated day (similar results even No control group in patients divided into manic and depressed groups) Kay et al., 1984 A 28-d DBPCT with 61 BD female Manic participants responded better to lithium Vitamin C could be important in the Small sample patients: than to vitamin C (43.3 vs 70.6) in the Beigel co-treatment of bipolar depression, but Withdrawn patients 29 manic (13 were medicated with rating scale the results do not support for mania 800 g/d lithium and 16 received 4 g There was no significant difference in vitamin C + 4 g EDTA) depression symptoms between amitriptyline 32 depressed (14 were medicated or vitamin C in the depressed group on with 150 mg amitriptiline and18 HAM-D (8.4 vs 10.7) and BDI (16.6 vs 19.8) received 4 g vitamin C + 4 g EDTA) ratings Vitamin D Sikoglu et al., 2015 An 8-week open label trial of Decrease in YMRS scores 43% improvement in manic symptoms Open label adjunctive treatment with vitamin Decrease in CDRS scores Small sample D (2000 IU) of 16 BD patients (6-17 Significant increase in anterior cingulate cortex Medication effects as a y old) in manic phase (ACC) glutamate, and γ-aminobutyric acid confounding factor measured with PMRS Pereira et al. | 555 Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/550/4955527 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Table 1. Continued Studies Findings Conclusion Limitations NAC Vitamin B9 (folic acid) Behzadi et al., 2009 A 3-week DBPRCT of adjunctive Statistically significant difference in YMRS Folic acid use as augmentation to Short follow-up treatment of folic acid (+valproate) scores between BD group and control groups valproate showed better response in BD of 88 BD manic patients (7.1 ± 0.9 vs 10.1 ± 1.1) patients in treatment of acute mania Coppen et al., 1986 A 52-week DBPRCT of adjunctive 21 patients with plasma folate concentration Lower treatment of 200 μg folic acid ≤12.9 ng/mL had a higher Beck score plasma folate concentrations can be (+lithium) of 75 BD (n = 17), MDD, (6.6 + 1.7) than the 18 patients with plasma correlated with higher affective and schizoaffective patients folate concentration >13.0 ng/mL (3.5 + 0.8) morbidity Daily supplement of folic acid could be helpful in long-term lithium prophylaxis Nierenberg et al., 2017 A 6-week open label of adjunctive 55% improvement in depression symptom in Potential as BD adjunctive treatment treatment with L-methylfolate MADRS and small mean decrease in YMRS (15 mg/d) of 10 BD patients in depressive phase Choline Stoll et al., 1996 Collection of 6 case reports of choline 5 patients had reduction of manic symptoms Choline was well tolerated in all cases and augmentation of lithium in rapid- 2 patients had improvement on depressive in combination with lithium could be an cycling BD patients symptoms effective therapy Choline responders exhibited a basal ganglia rise in concentration of choline-containing compounds Lyoo et al., 2003b A 12-week DBT of adjunctive No significant differences in change-from- Adjuvant treatment with choline resulted treatment of choline (+lithium) of 8 baseline measures of CGI, YMRS, or HAM-D in lower purine levels and increased rapid-cycling BD patients Choline-treated group showed decreased brain membrane phospholipid synthesis purine levels compared with placebo 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 pres- sure; 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. 556 | International Journal of Neuropsychopharmacology, 2018 NAC compared with placebo (Magalhães et al., 2011b). The looking at CoQ10 supplementation and BD. One study explored investigation of those experiencing mania indicated within- CoQ10 in combination with other mitochondrial agents (such as group improvements in the NAC group (Magalhães et al., 2013). NAC and b-group vitamins) as an adjunctive treatment for bipo- Similarly, when exploring a subgroup of participants (n = 14) lar depression (Dean et al., 2015). This study has been completed with bipolar II (divided in 2 groups of 7 patients each rand- but results are still pending. omized to placebo or NAC), NAC was found to improve symp- Forester et al. (2012) investigated an 8-week intervention of toms in 6/7 participants, compared with 2/7 in the placebo CoQ10 in a sample of 10 outpatients aged 55 years and older group (Magalhães et al., 2011a). NAC was also shown to improve with a DSM-IV diagnosis of bipolar depression in an 8-week functional outcomes for people experiencing cardiovascular or study. Participants were administered CoQ10 and compared endocrine comorbidities when compared to those who did not with 8 healthy controls who did not receive CoQ10 supplemen- (Magalhães et al., 2012). Finally, a paper on posthoc analyses has tation. The maximum dose of CoQ10 was 1200 mg/d, starting at reported no change in cognition in a small subset of participants 400 mg/d and titrated up by 400 mg/d every 2 weeks. Participants following NAC (Dean et al., 2012). on CoQ10 showed modest but significant improvements in The next study included a maintenance design with an ini- their depression symptoms (measured on the Montgomery– tial open-label phase. Participants were given 2000 mg/d of NAC Åsberg Depression Rating Scale MADRS) over the 8-week study. (n = 149) for a total of 8 weeks and were then randomized to con- Furthermore, this study also investigated mitochondrial func- tinuation of adjunctive NAC treatment or a placebo. The open- tion via phosphorus magnetic resonance spectroscopy and label phase showed significant improvements in participants reported no significant differences between groups for creatine experiencing bipolar depression (Berk et al., 2011). However, in kinase (a mitochondrial protein). This small study is limited by the maintenance (randomized) phase, participants in both arms the sample size and lack of placebo control but highlights the generally stayed well, which resulted in no significant treatment potential of CoQ10 as an antidepressant and treatment for BD. effects (Berk et al., 2012). We further searched ANZCTR and Clinicaltrials.gov to ascer - Alpha-Lipoic Acid tain if there are upcoming studies in this area. A protocol has Alpha-lipoic acid (ALA), also known as thioctic acid, is a pleio- been published describing a study of NAC and a combination tropic substance (Gomes and Negrato, 2014). ALA is a strong of other agents that enhance mitochondrial function, compared antioxidant (Suzuki et al., 1991; Moini et al., 2002). It increases with placebo, over 16 weeks of treatment (Dean et al., 2015). levels of glutathione (Han et al., 1997; Yamada et al., 2011; Overall, NAC is a potentially useful adjunctive therapy Kleinkauf-Rocha et al., 2013), raises hepatocyte ascorbate lev- for BD and, in particular, bipolar depression during the acute els (Lykkesfeldt et al., 1998; Michels et al., 2003), downregulates phase. NAC has been shown to enhance mitochondrial func- nuclear factor kappa-light-chain-enhancer of activated B cells tion in preclinical models. However, no clinical studies that have (DeMarco et al., 2004), and is a metal chelator (Ou et al., 1995; investigated NAC for BD have evaluated outcomes related to Suh et al., 2005), an antiviral in glial cells (Scumpia et al., 2014), mitochondrial function. Further research is required to explore and a glucose uptake promoter (Estrada et al., 1996; Henriksen the interactions of NAC clinical efficacy and changes in rele- et al., 1997; Saengsirisuwan et al., 2004), increasing GLUT4 levels vant pathways, including pathways relevant to mitochondrial and insulin action (Hughes et al., 1993). Relevant to the current function. review, ALA also has a role as a mitochondrial agent. It can be endogenously synthesized in the mitochondria where it acts as Coenzyme Q10 a coenzyme for the formation of pyruvate dehydrogenase and Coenzyme Q10 (CoQ10), also known as ubiquinone, is a power- α-ketoglutarate—both essential components of the Krebs cycle. ful lipid-soluble antioxidant that reduces the flow of electrons Because pyruvate dehydrogenase converts pyruvate to acetyl on the ROS-producing regions of Complex I, II, and III of the CoA, ALA decreases lactate levels, thus inhibiting glycolysis mitochondria (Lenaz et al., 2002; Nierenberg et al., 2013). CoQ10 (Gomes and Negrato, 2014). It also modulates the key regulator reduces ROS by neutralizing the free radical alpha-tocopheroxyl of mitochondrial biogenesis, peroxisome proliferator-activated to alpha-tocopherol (vitamin E) and plays a role in the bio- receptor-gamma coactivator-1alpha (PPAR-GC-1α) (Liu, 2008). synthesis of adenosine triphosphate (ATP) (Morris et al., 2013; PPAR-GC-1α stimulation has been linked to neuroprotection and Nierenberg et al., 2013). The genes associated with these com- its suppression to mitochondrial dysfunction and neurodegen- plexes and the transportation of electrons across them are eration (Cui et al., 2006; St-Pierre et al., 2006). ALA also affects expressed differently in BD compared with healthy controls the mitochondrial pathway of apoptosis, prompting research in (Sun et al., 2006b). Supplementary CoQ10 has poor oral bioavail- oncology as an agent with antimetastatic potential (Dörsam and ability; however, it does cross the blood-brain barrier (Matthews Fahrer, 2016). This provides a rationale for its action in mood and et al., 1998). cognitive disorders. Morris et al. (2013) discussed the reduction in CoQ10 levels In a corticosterone-induced model of depression in mice, ALA in psychiatric and mitochondrial disorders such as depres- showed antidepressant properties and reversed brain-derived sion, chronic fatigue syndrome, fibromyalgia, and Parkinson’s neurotrophic factor reduction in the hippocampus and striatum disease and postulated that CoQ10 supplementation could be (de Sousa et al., 2015). In a d-amphetamine-induced model of a treatment for these disorders. However, a meta-analysis of mania, ALA was able to both prevent and reverse symptoms CoQ10 supplementation compared with placebo showed no with comparable efficiency to lithium (Macêdo et al., 2012). significant benefits for participants with Parkinson’s disease Only one clinical trial has explored ALA as an adjunctive (Negida et al., 2016). treatment for bipolar depression. The trial tested a combina- There have been several studies proposing the use of CoQ10 tion of ALA (600–1800 mg/d) and acetyl-L-carnitine (ALC) (1000– supplementation as a mitochondrial enhancing agent in gen- 3000 mg/d) or placebo for 12 weeks in 40 participants with bipolar eral and for BD in particular (Morris et al., 2013; Nierenberg depression. Previous treatment (stable for at least 4 weeks) was et al., 2013). Despite this, there have been only 2 studies directly continued. The primary outcome was depression, measured on Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/550/4955527 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Pereira et al. | 557 the MADRS. No significant changes were found between groups (type I and II) was conducted. To enroll, subjects were required (Brennan et al., 2013). As the authors note, the shorter duration to have not responded previously to either 2 antidepressants (of of the study (12 weeks) compared with a positive RCT of a mito- different classes) or to 2 different mood stabilizers. No signifi- chondrial agent (NAC) in BD (24 weeks) (Berk et al., 2008), the cant differences were observed in MADRS, Hamilton Rating Scale inclusion of bipolar I and II types, concomitant medication use, for Depression (HAM-D), or Young Mania Rating Scale (YMRS) and possible low oral bioavailability of the agents are all poten- between the SAMe and placebo groups. No switches to mania tial confounders that should be addressed. were reported (Murphy et al., 2014). Carney et al. (1989) reported More research is required to determine the efficacy of 3 open label trials and 1 placebo-controlled trial after a drug- ALA in BD. Moreover, there is one study (described earlier) in free period of at least 7 days. There were 14 unipolar depression bipolar depression that is currently being completed that and 11 BD participants. Nine of the 11 BD participants switched includes a combination of agents including ALA, ALC, and NAC to hypomania, mania, or “elevated mood.” The other 2 partici- (ACTRN12612000830897). pants did not respond to treatment (Carney et al., 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 ALC case reports of mood switch in BD patients, 1 of mania, and 1 of In addition to the role of ALC in mitochondrial β-oxidation and hypomania (Lipinski et al., 1984). Due to the potential for manic energy production (Hoppel, 2003), ALC has antioxidant properties switching, SAMe for BD should be investigated with caution. In (Gülçin, 2006; Mescka et al., 2011). Additionally, ALC has been pro- unipolar depression, a meta-analysis in 2002 showed that SAMe posed to mediate the transfer of acetyl groups for acetylcholine is superior to placebo improving HAM-D scores (Hardy et al., synthesis, modulate nerve growth factors and gene expression 2003). A recent systematic review collected clinical information (Nałecz and Nałecz, 1996; Binienda, 2003; Nacz et al., 2004), and from 115 clinical trials and 17 preclinical studies on the effect of counter glutamate-induced excitotoxicity (Zanelli et al., 2005). SAMe on several neuropsychiatric conditions. Positive but lim- Data from animal models provide further evidence for ALC’s ited evidence was found for the use of SAMe in major depressive therapeutic potential due to its role as an antioxidant and in disorder (MDD) as both a monotherapy and adjunctive therapy improving mitochondrial energy production (Rao et al., 1997; (Sharma et al., 2017). Recently, 2 studies have demonstrated Aureli et al., 1998; Hagen et al., 2002b; Al-Majed et al., 2006), its benefits of SAMe as an augmentation antidepressant therapy. neuroprotective action in trauma (Karalija et al., 2014) and ische- In a 6-week, double blind, placebo RCT with serotonin reuptake mia (Rosenthal et al., 1992; Barhwal et al., 2007), its antidepres- inhibitors or serotonin norepinephrine reuptake inhibitors non- sant effect in the forced swim test (FST) (Wang et al., 2015), and responders, participants undergoing SAMe augmentation had its ability to reverse memory loss in older rats (Liu et al., 2002). lower HAM-D score and higher remission rates (final HAM-D Two patients with geriatric depression treated with ALC score <8) than placebo (Papakostas et al., 2010). showed increases in PCr and β-nucleoside triphosphate (β-NTP) levels (Pettegrew et al., 2002). PCr serves as a reservoir for high- Creatine Monohydrate energy phosphates, and β-NTP is acknowledged as an index of brain levels of ATP. Thus, these results provide support for a link Creatine is the precursor of PCr. Long-term decrease of PCr between the antidepressant action of ALC and improved energy decreases ATP production, attributable to mitochondrial dys- production within the brain. function (Erecińska and Silver, 1989). Oral supplementation However, the only RCT in BD reported no effect when admin- of creatine monohydrate increases creatine and brain con- istered in combination with ALA (Brennan et al., 2013) (see centrations of PCr (Dechent et al., 1999; Lyoo et al., 2003a). In above). Furthermore, the change in PCr and β-NTP, previously BD, decreased PCr concentrations have been reported (Stork found in geriatric depression patients (Pettegrew et al., 2002), and Renshaw, 2005). Furthermore, creatine has been shown was not observed (Brennan et al., 2013). Two case reports of ALC- to have antioxidant properties in animal models of oxidative associated relapse in BD also suggest some caution with clin- stress (Sullivan et al., 2000; Tarnopolsky and Beal, 2001; Lawler ical use. The first case-reports detail a psychotic episode in a et al., 2002) known BD type I patient, 5 days after starting treatment with A 4-week open-label trial with 10 participants experienc- nutritional supplements including vitamin C, vitamin E, and ing treatment-resistant depression (8 unipolar and 2 bipolar) ALC (500 mg/d) (Evcimen et al., 2007). Manic symptoms associ- showed improved depression scores with 3 to 5 g/d creatine ated with self-prescribed ALC treatment (2000 mg/d) in a man monohydrate augmentation, provoking switch to elevated mood with BD type I resolved 3 days after cessation of ALC (Goodison in both BD patients (Roitman et al., 2007). Two trials focusing et al., 2016). 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 S-Adenosylmethionine of creatine monohydrate as an adjunctive therapy for BD type S-Adenosylmethionine (SAMe) results from the combination I depression (NCT01655030) is also currently recruiting. of ATP and methionine and plays a crucial role as a methyl donor in reactions involving methyltrasnferases (Bottiglieri, Melatonin 2002). SAMe is also a precursor molecule for glutathione pro- duction, which plays an essential role in reducing oxidative Melatonin regulates several homeostatic processes such as cir - stress. In the brain, SAMe repairs and degrades proteins and cadian rhythm maintenance, growth hormone stimulation, and activates thyroxine hydroxylase through methylation, which insulin secretion (Paredes et al., 2014; Simões et al., 2016; Zhang is critical in the synthesis and regulation of monoamines (i.e., et al., 2016). Relevant to mitochondrial physiology, melatonin dopamine, serotonin), which are known to be dysregulated in BD improves oxidative phosphorylation, increasing the activity of (Bottiglieri et al., 2000, 2002). Recently, an RCT of SAMe as an add- the I and IV dose-dependent complexes and membrane fluid- on to an approved mood stabilizer in 20 participants with BD ity and closes the mitochondrial permeability transition pore Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/550/4955527 by Ed 'DeepDyve' Gillespie user on 21 June 2018 558 | International Journal of Neuropsychopharmacology, 2018 (a protein complex spanning the inner and outer mitochon- were treated with lithium or valproic acid for at least 6 weeks drial membranes), preventing ATP depletion and necrotic cell were randomized to treatment with agomelatine or placebo death (Acuña-Castroviejo et al., 2001, 2007; Martín et al., 2002; (n = 172 each group) in a double-blind study (Yatham et al., 2016). Leon et al., 2005). Moreover, melatonin and some of its metabo- No significant differences between both groups in MADRS total lites play an important antiinflammatory and antioxidant role score or response or remission rates from baseline to endpoint through scavenging oxygen and nitrogen-based ROS (López- were found. The number of manic or hypomanic symptoms was Burillo et al., 2003; Korkmaz et al., 2009). Melatonin directly comparable between both groups at each assessment time. As a boosts mRNA expression of genes implicated in the production number of sites had placebo response rates of 100%, when these of glutathione peroxidase and superoxide dismutase, 2 antioxi- were excluded in a posthoc analysis, a signal favoring agomela- dant enzymes (Rodriguez et al., 2004; Acuña-Castroviejo et al., tine over placebo emerged. While the meta-analyses in unipolar 2007; Anderson and Maes, 2014). Furthermore, peripheral mela- depression confirm the antidepressant effects of agomelatine tonin, produced outside the brain, is decreased in BD compared (Singh et al., 2012; Taylor et al., 2014), melatonin supplementa- with healthy controls, suggesting supplemental melatonin may tion did not significantly improve treatment or prophylaxis of be a relevant intervention in this population (Anderson and unipolar depression (Hansen et al., 2014). Maes, 2014). In an 8-week, double blind, placebo control trial, 44 par- Pyrimidines ticipants (24 participants with SZ and 20 with BD) treated with The pyrimidine nucleosides such as uridine, triacetyluridine, and second-generation antipsychotics received low dosages of mela- cytidine have effects on mitochondrial function, glutamatergic tonin (5 mg/d) and placebo. The melatonin group showed lower transmission, catecholamine synthesis, and cerebral phospho- diastolic blood pressure and less weight gain, these results being lipid metabolism, which has been linked to the pathophysiology greater in the BD group (Romo-Nava et al., 2014). In an open- of BD (Yoon et al., 2009; Kondo et al., 2011). Uridine (1000 mg/d) label trial, melatonin improved mania scale scores and sleep- was studied in a 6 weeks open-label trial of 7 teenagers with ing patterns (Bersani and Garavini, 2000) but had no significant bipolar depression. Children’s Depression Rating Scale-Revised effects on mood or sleep in a double-blind, placebo-controlled and the Clinical Global Impressions scale were used to measure trial using the same dose with 5 rapid-cycling DSM-III-R BD the treatment results. Uridine was well tolerated and depressive patients (Leibenluft et al., 1997). symptoms decreased (Kondo et al., 2011). McElroy et al. (2011) tested ramelteon (a highly selective In another 6-week study (n = 20), 18 g/d day of triacetyluridine melatonin MT1/MT2 receptor agonist) as an adjunctive treat- (TAU), a uridine prodrug, or placebo was given to patients with ment in 21 outpatients with bipolar I disorder with mild-to- bipolar depression. BD patients who had a reduction in MADRS moderate manic symptoms and sleep disturbance in an 8-week, scores ≥50% showed a greater difference in pH changes (assessed double-blind, fixed-dose (8 mg/d) study. A global improvement by phosphorus magnetic resonance spectroscopic imaging in a global rating of depressive symptoms was reported; how- (PMRSI)) compared with TAU nonresponders, suggesting that ever, no significant differences in ratings of insomnia, mania, TAU treatment can have benefits in depressive symptoms and in and global severity of illness were observed. Norris et al. (2013) mitochondrial function (Jensen et al., 2008). Cytidine, available conducted a double-blind, randomized, placebo-controlled trial from dietary sources and converted in uridine in the human of adjunctive ramelteon in euthymic bipolar patients with sleep body, was investigated in a 12-week, randomized, placebo trial disturbances and reported that participants receiving ramelteon with 35 patients with bipolar depression. Participants were ran- were significantly less likely to relapse compared with placebo. domly given valproate plus placebo or valproate plus cytidine. Recently, a RCT comparing placebo with sublingual ramelteon in At 2, 4, and 12 weeks, the cerebral levels of glutamate/glutamine different dosages (0.1 mg, 0.4 mg, 0.8 mg, once daily) as adjunct- were measured using PMRSI. The results showed that cytidine ive maintenance therapy in stable BD patients did not show sig- supplementation resulted in earlier improvement in symptoms nificant differences between any dose of ramelteon and placebo of depression and greater reduction in glutamate/glutamine lev- (Mahableshwarkar et al., 2017). The study was terminated before els. These data suggest that the observed therapeutic effect of the expected sample size due to meeting the futility criteria. All cytidine may be mediated via a decrease in cerebral glutamate/ studies showed ramelteon was well tolerated and associated glutamine levels (Yoon et al., 2009). with no serious adverse events. Agomelatine (an agonist of melatonin 1 and 2 receptors and antagonist of serotonin 2C receptors drug) has also been inves- Choline tigated as an adjunctive treatment for bipolar depression. In an Choline is a constituent of the neurotransmitter acetylcholine, open-label trial with 21 type I BD patients in a severe depres- a major methyl-donor, and needed for structural integrity and sive episode (14 treated with lithium and 7 with valpromide), intracellular signaling within cell membranes. In an open-label agomelatine was added at 25 mg/d for at least 6 weeks and, if trial, Stoll et al. (1996) studied the effects of lithium augmenta- participants opted-in, up to 1 year. At week 6, 81% of patients tion with choline in 6 rapid-cycling BD outpatients. Five partici- improved >50% in HAM-D score from baseline and almost 50% pants experienced a reduction in manic symptoms and 4 had in the first study week. Three patients switched to mania or a reduction in all mood symptoms during choline therapy. The hypomania from the sixth week until the complete year fol- impact on depression was variable. Lyoo et al. (2003b) studied 8 low-up (Calabrese et al., 2007). In a similar study, 28 type II BD lithium-treated, rapid-cycling BD I and II patients randomized patients in a severe depressive episode (11 treated with lithium to receive either choline or placebo, and reported significantly and 17 with valproate) were treated with agomelatine at fixed decreased brain purine levels, a marker of energy metabolism. dosages of 25 mg/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 Vitamin A 4 drop-outs in total due to polarity change (1 manic and 3 hypo- manic episodes) (Fornaro et al., 2013). Recently, 344 type I BD Both deficient and excessive levels of vitamin A disrupt many patients undergoing a current major depressive episode that human systems, including the central nervous system (CNS) Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/550/4955527 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Pereira et al. | 559 (Chapman, 2012). Vitamin A is required for vision, gene tran- Vitamin D scription, immune system, and skin cell differentiation Vitamin D is a fat-soluble antioxidant involved in the regula- (Haybaeck et al., 2015). The role of vitamin A in gene expres- tion of calcium and phosphate metabolism. Moreover, vitamin sion and its role in redox activation suggest a possible role as D is implicated in the production of melatonin and in seasonal a mitochondrial agent in the treatment of BD. Vitamin A also affective disorder (Gloth et al., 1999). The association between plays a very important role as a co-factor in redox activation, low levels of vitamin D and mood disorders (MDD, BD, and dys- binding to protein kinase C (Hoyos et al., 2012; Hammerling, thymia) has been established (Anglin et al., 2013; Belzeaux et al., 2016). Retinoid receptors are concentrated in the striatum, 2015), and it was also identified as a risk factor for develop- hippocampus, frontal cortex, and hypothalamus, all key brain ment of postpartum depression in pregnant women (Robinson areas involved in depression (Bremner et al., 2012). Being et al., 2014). Furthermore, vitamin D influences monoamine involved in neuroplasticity in the hippocampus, vitamin metabolism by modulating the hypothalamic-pituitary-adrenal A deficiency can also affect memory, appetite, and growth axis through vitamin D receptors (VDRs) (Puchacz et al., 1996; (Haybaeck et al., 2015; Stoney and McCaffery, 2016). Haybaeck Prüfer et al., 1999; Eyles et al., 2005). VDRs also affect nuclear et al. (2015) found the brains of patients with SZ, BD, or MDD to transcription, regulate the expression of the dopamine receptor have significantly increased expression of vitamin A-inducible gene (Trinko et al., 2016), and may also be involved in the regu- or induced gene 1, pointing to altered signaling pathways. lation of mitochondrial function and lipid metabolism (Silvagno Another study found mRNA levels of key elements of vita- and Pescarmona, 2017). VDR is now known to translocate into min A signaling were significantly reduced in the postmortem mitochondria, which raises the possibility of vitamin D having dorsolateral prefrontal cortex/anterior cingulate cortex from a direct impact on cellular bioenergetics by altering mitochon- elderly depressed patients (Qi et al., 2015). A similar signal was drial function and VDR to work as a modulator of energy balance detected in a chronic unpredictable mild stress model in rats in humans (Silvagno and Pescarmona, 2017). Studies on cancer (Qi et al., 2015). There is evidence of a link between isotreti- cells (Consiglio et al., 2014), keratinocytes (Consiglio et al., 2015), noin use and depression and suicide (Bremner et al., 2012; Hu adipocytes (Ricciardi et al., 2015), and VDR-null mutant mice et al., 2016), clinical exacerbation of BD, and possibly to psych- (Wong et al., 2011) found that VDR can influence the transcrip- osis (Ludot et al., 2015). Vitamin A therapy at high doses is also tion of proteins of the mitochondria respiratory chain, inhibiting associated with cognitive decline (de Oliveira et al., 2009; 2015) it and redirecting Krebs cycle intermediates toward biosyn- and increased levels of oxidative stress markers in both human thesis (Consiglio et al., 2014). However, establishing the treat- and animals (de Oliveira et al., 2009). ment effect of vitamin D supplementation has been somewhat problematic as studies are likely too heterogeneous (including Vitamin C depression, seasonal affective disorder, obesity, postmenstrual tension, and hospitalized patients). Therefore, varying the selec- Vitamin C is an antioxidant capable of scavenging free radi- tion criteria wields both positive and negative meta-analysis cals and other ROS formed in cell metabolism. In addition to results: A meta-analysis of 15 RCTs (with samples between 15 its role as an antioxidant, vitamin C is a co-substrate of many and 2117) was favorable for vitamin D supplementation (≥800 important oxidoreductases and may regulate gene transcrip- I.U. daily) (Spedding, 2014), while another meta-analysis using tion (Arrigoni and de Tullio, 2002). Because of these characteris- 6 RCTs (n = 1203, 71 depressed) showed no significant effect of tics, vitamin C has been tested as a possible adjunctive therapy vitamin D supplementation on postintervention depression in psychiatric disorders. A double-blind, placebo RCT in high scores (Li et al., 2014). A more recent double-blind RCT of 40 school students showed lower levels of anxiety after 14 days of MDD patients on vitamin D monotherapy (50 kIU/d for 8 weeks) vitamin C supplementation compared with placebo (de Oliveira showed beneficial effects on the depressive symptoms meas- et al., 2015). Positive results were also reported in a 6-month, ured by the BDI on indicators of glucose homeostasis and on double-blind, randomized control pilot trial with 1000 mg/d oxidative stress levels (Sepehrmanesh et al., 2016). Regarding vitamin C as an adjunct to 10 to 20 mg/d fluoxetine in children BD, an 8-week open-label trial tested the effect of adjunctive (n = 24) diagnosed with MDD (Amr et al., 2013). However, the vitamin D supplementation in mania in young bipolar spectrum only RCT testing vitamin C as an adjuvant (1000 mg/d) in the disorder patients (aged 6–17 years old). There was a significant treatment of adults (n = 43) with MDD (added to 60 mg/d cit- decrease in YMRS scores and improvement in levels of glutam- alopram) showed no statistically significant results (Sahraian ate and γ-aminobutyric acid (GABA) measured in the anterior et al., 2015). cingulate cortex (Sikoglu et al., 2015). In BD, vitamin C was proposed as a treatment in a dou- ble-blind, placebo control cross-over trial, where 23 BD par- ticipants receiving 3 g/d of vitamin C reported improvement Vitamin E in depressive symptoms (Naylor and Smith, 1981). Kay et al. (1984) conducted a 28-day, double-blind, randomized active- Vitamin E or tocopherol is a fat-soluble antioxidant, which has a control study with 61 BD inpatients (29 with manic symptoms stabilizing function in the mitochondrial membrane attributed and 32 with depressive symptoms). The depressed participants to radical scavenging and lipid peroxidation reduction (Kagan received either 150 mg/d amitriptyline (n = 14) or 4 g/d vitamin et al., 1990; Pham-Huy et al., 2008). Studies have suggested C plus 4 g/d ethylene diamine tetra acetic acid (EDTA) (n = 18). that vitamin E may be more effective when combined with The manic participants were also divided into 2 groups—13 CoQ10 or vitamin C (Kontush and Schrkatolina, 2004; Dhitavat were medicated with 800 g/d lithium and 16 received only vita- et al., 2005). To our knowledge, the efficacy of vitamin E in BD min C plus EDTA. Manic participants responded better to lith- or MDD has not been examined. Some animal studies found ium than to vitamin C. There was no significant difference in positive results—chronic administration of high doses of vita- depression symptoms between amitriptyline or vitamin C in min E improved lifespan, neurological performance, and brain the depressed group on HAM-D and Beck Depression Inventory mitochondrial function in aging mice (Navarro et al., 2005). (BDI) ratings. Likewise, studies in Alzheimer’s disease are also promising. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/550/4955527 by Ed 'DeepDyve' Gillespie user on 21 June 2018 560 | International Journal of Neuropsychopharmacology, 2018 A multi-center RCT studied the effect of vitamin E supplemen- of L-methyfolate was given for 60 days. The second trial had tation in 613 participants with mild-to-moderate Alzheimer’s positive results on primary outcomes—degree of improvement disease, medicated with memantine, and reported slower func- in depressive symptom score and response rate (Papakostas tional decline and decreased caregiver burden (Dysken et al., et al., 2012). Folic acid was also found to improve the therapeutic 2014). A cross-sectional and prospective study of 104 patients effect of fluoxetine in depressed patients in another 2 placebo- with Alzheimer’s disease showed reduced prevalence and inci- controlled RCTs. Studies with samples of 127 and 42 patients dence of Alzheimer’s on those consuming vitamin E plus C sup- with MDD, respectively, were treated with folic acid plus 20 mg plementation (Zandi et al., 2004). A clinical trial with combined of fluoxetine and showed greater improvement in the HAM-D therapy with vitamin C for MDD in elderly patients is now in the and in the BDI (Coppen and Bailey, 2000; Venkatasubramanian recruiting phase (NCT02793648). et al., 2013). Moreover, long-term treatment of post-stroke sur - vivors (n = 273) with folic acid, B6, and B12 was associated with a reduction in the risk for MDD (Almeida et al., 2010). The effect Vitamin B Complex of vitamin B9 as a possible early intervention was studied in a The vitamin B complex contains water-soluble vitamins B1, double-blind, placebo RCT in healthy teenagers (n = 112) with B2, B3, B5, B6, B7, B9, and B12. They play an important role in a increased familial risk of depression and BD. Folic acid did not variety of critical brain pathways and participate in mitochon- reduce the incidence of a mood disorder diagnosis but may have drial energy production and cellular function (Dean et al., 2012). delayed the first mood episode and its clinical presentation Vitamin B complex is known to influence cognitive performance tended to be milder (Sharpley et al., 2014). and mood. Its influence in CNS function has been suggested to occur in 2 interrelated ways: direct via of hypomethylation Vitamin B1 and indirectly by homocysteine levels resulting in structural Vitamin B1, or thiamine, functions as a cofactor essential for the changes in the brain (Calvaresi and Bryan, 2001). They often oxidative decarboxylation of the Krebs cycle (Depeint et al., 2006). work in synergy and thereby are best administered as a complex Vitamin B1 deficiency is associated with neurological problems, (Dean et al., 2012). including cognitive deficits and encephalopathy (Depeint et al., 2006; Gibson et al., 2016). Healthy elderly women with marginal Vitamin B9 vitamin B1 deficiency experienced with thiamin supplementa- Vitamin B9, or folate, is involved in the synthesis, repair, and tion a significant increase of appetite, body weight, energy, and methylation of DNA and in the formation of monoamine neu- activity, and decreased fatigue, improvement of sleep patterns, rotransmitters, thus being important in the pathogenesis of and of general well-being (Smidt et al., 1991). affective disorders (Mattson and Shea, 2003; Folstein et al., 2007; Miller, 2008; Sharpley et al., 2014). Together with vitamin B12, Vitamin B3 vitamin B9 plays an essential role in mitochondrial energy pro- Vitamin B3, or niacin, is a precursor for NADH and nicotinamide duction through 1-carbon transfer pathways (Dean et al., 2015). adenine dinucleotide phosphate, which is involved in more than Folate deficiency has been associated with several neuropsychi- 500 enzymatic reactions pertaining to mitochondrial respira- atric disorders, especially in inpatients (Hall et al., 1997; Dean tion (oxidative phosphorylation), glycolysis, and lipid oxidation et al., 2015) such as depression, BD, and cognitive dysfunction (Depeint et al., 2006). The potential of NADH as an antidepres- (Bell et al., 1990; Godfrey et al., 1990; Hasanah et al., 1997; Selhub sant was first tested in the FST model in Wistar rats, yielding et al., 2000; Bryan et al., 2002; Reynolds, 2002; Gilbody et al., a similar effect to fluoxetine (Rex et al., 2004). Vitamin B3 sup- 2007). Furthermore, in long-term lithium-treated patients, low plementation was also shown to prevent development and pro- serum folate levels were associated with higher affective mor - gression of mitochondrial myopathy in mice (Khan et al., 2014). bidity (Coppen and Abou-Saleh, 1982). Schou et al. (1986) also More relevant to BD, evidence of mood elevation was reported found low levels of folate in untreated BD patients (25% lower in a 54-year-old man with no previous mental illness, who had than controls) and their normalization after 6 months of lith- a manic episode after commencing vitamin B3 for his dyslipi- ium. Behzadi et al. (2009) conducted a preliminary RCT with 88 demia (Loebl and Raskin, 2013). BD type I manic patients treated with sodium valproate and adjuvant folic acid (synthetic form of folate). After 3 weeks, Vitamin B6 a statistically significant difference in the YMRS was found. Vitamin B6 refers to 3 primary forms: pyridoxine, pyridoxal Another double-blind RCT of 75 lithium-treated BD patients phosphate, and pyridoxamine. The last 2 serve as coenzymes on a daily supplementation of 200 μg folic acid for 52 weeks for protein metabolism, conversion of tryptophan to niacin, and showed a significant reduction in affective morbidity (Coppen neurotransmitter function. Some of the protective effect of vita- et al., 1986). L-methylfolate was also recently studied in the first min B6 may occur via modification of mitochondrial function open-label trial for bipolar depression. Ten patients with BD by preventing the oxygen radical generation and lipid peroxida- type I on standard treatment for bipolar depression (but with tion (Kannan and Jain, 2004). Higher dietary intake of vitamin no antidepressant) received 15 mg of folate daily for 6 weeks. B6 and folate was associated with lower prevalence of depres- A 55% improvement in depression symptom ratings (MADRS) sion symptoms (measured with the Center for Epidemiologic and a small mean decrease in YMRS was found, suggesting Studies Depression Scale) in a large cross-sectional study of its potential as BD adjunctive treatment (Nierenberg et al., 6517 community adolescents (aged 12 to 15) (Murakami et al., 2017). L-methylfolate has potential as an adjunctive treatment 2010). Another study in 38 healthy older men on 20 mg of vita- for unipolar depression. Two multicenter sequential parallel min B6 supplementation showed cognitive benefits such as comparison design trials were conducted with MDD patients improved memory but failed to improve mood (Deijen et al., (n = 148 and n = 75) with partial or no response to serotonin 1992). A double-blind RCT in 211 healthy women showed simi- reuptake inhibitors. L-methylfolate supplementation was given lar results (Bryan et al., 2002). Another 4-week, double-blind RCT for 30 days at the dosing of 7.5 mg/d and augmented later to with 14 geriatric depressed inpatients tested the augmentation 15 mg/d in the following month in trial one. In trial two, 15 mg/d of tricyclic antidepressant treatment with vitamins B1, B2, and Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/550/4955527 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Pereira et al. | 561 B6 (10 mg/d). The active vitamin group demonstrated greater a case-report of an acute onset of mania in a 94-year-old man improvement in scores on ratings of depression and cognitive with no previous mental illness and profound cobalamin defi- function (Bell et al., 1992). A 24-week, open-label clinical trial ciency who responded to cobalamin therapy (Jacobs et al., 1990). with 10 participants with SZ patients that were already receiving In a double-blind RCT of vitamin B12 supplementation in win- antipsychotics were given 1200–2400 mg/d of pyridoxamine. The ter seasonal affective disorder, no significant differences were patients had high levels of plasma pentosidine, a carbonyl stress found (Oren et al., 1994). No benefit for B12 replacement was biomarker. The results were measured with the Positive and found in cognitive symptoms in dementia (van Dyck et al., 2009) Negative Syndrome Scale score and the Brief Psychiatric Rating or depressive symptoms in an elderly man (Ford et al., 2008). Scale. Treatment augmentation with pyridoxamine showed partial results in participants with enhanced carbonyl stress; Other Potential BD Agents however, only 3 patients had reduction of psychopathology. Taurine Four patients showed improvement on iatrogenic parkinson- Taurine is a free amino acid that has important functions as a ism. However, 2 patients had Wernicke’s encephalopathy-like neuromodulator and antioxidant. It protects against glutamate- adverse drug reactions, reversed by thiamine supplementation induced neurotoxicity and has been hypothesized to prevent (Itokawa et al., 2018). membrane depolarization and mitochondrial energy failure (Timbrell et al., 1995; Ye et al., 2013). Recently, taurine has been Vitamin B2 reported to reduce oxidative stress and maintain mitochon- Vitamin B2 is a precursor of flavin adenine dinucleotide and fla- drial function in cortical neurons (Xu et al., 2015). Moreover, vin mononucleotide and is required for electron transport chain taurine acts as an agonist for glycine and γ-aminobutyric acid in complexes I and II. They work synergistically with other B receptors (Albrecht and Schousboe, 2005). In the FST model in vitamins for mitochondrial respiration (Depeint et al., 2006). rats, taurine supplementation has antidepressant-like effects Henriques et al. (2016) showed that vitamin B2 supplementa- (Toyoda and Iio, 2013). In a double-blind RCT in people with first- tion could functionally compensate for mitochondrial ß-oxida- episode psychosis, taurine improved symptoms of depression tion enzymes. Four nonrandomized trials have been reported and reduced psychotic symptoms as well as improved measures effectively treating mitochondrial diseases with complex I and/ of functioning but failed to impact cognition (O’Donnell et al., or complex II (Bernsen et al., 1993; Bugiani et al., 2006; Gerards 2016). While a double-blind RCT in BD adolescents with a manic et al., 2011) and III and IV (Ghezzi et al., 2010) deficiency. episode was conducted (CT00391001), the study was terminated and no results have been published. Another double-blind RCT Vitamin B5 was carried out but despite its completion, no results have been Vitamin B5 is the precursor of CoA, important in the Krebs cycle revealed at this time (NCT00217165). and fatty acid oxidation. In vitro and in vivo studies suggest that vitamin B5 can restore ATP synthesis levels as well as the Bezafibrate activity of antioxidant enzymes and can prevent the collapse of An agonist of the PPAR usually prescribed as an hypolipidemic mitochondrial membrane potential (Depeint et al., 2006). There drug, bezafibrate can restore fatty acid oxidation activity in cells are established associations between vitamin B5 deficiency and from carnitine palmitoyltransferase-2 and very-long-chain acyl- neurodegenerative diseases, dermatitis, hypoglycemia, con- CoA dehydrogenase deficiencies in in vitro conditions (Bastin vulsions, and encephalopathy with liver failure (Depeint et al., et al., 2008). Data suggest that the PPAR signaling pathway is 2006). directly implicated in mitochondrial physiology. Exposure to bezafibrate increased the transcription of HADHA and HADHB Vitamin B7 genes (responsible the encoding of alpha and beta subunit of Vitamin B7 is a coenzyme for 5 mitochondrial carboxylases and the mitochondrial trifunctional protein) (Aoyama et al., 1998), is essential for growth, development, and normal mitochon- immune-detectable alpha and beta subunit proteins, activities drial and cellular functions, including fatty acid oxidation and of long-chain 3-hydroxyacylCoA dehydrogenase and long-chain gluconeogenesis. Reductions in vitamin B7 result in the loss of 3-ketoacylCoA thiolase, and stimulated fatty acid oxidation mitochondrial complex IV, which leads to increased production capacities in human fibroblasts (Djouadi et al., 2016). To the best of oxidative species by the mitochondria (Depeint et al., 2006). of our knowledge, no clinical data are available in the literature Several clinical disorders are associated with B7 deficiency, such regarding the role of benzafibrate in psychiatry. However, an as cutaneous conditions (skin rashes, alopecia, and conjunctivi- 8-week, open-label pilot trial of bezafibrate 400 mg/d added to tis), neurological conditions (depression, seizures, paresthesia), lithium in 20 participants with bipolar depression is being con- and diabetes (Depeint et al., 2006). ducted to assess its safety, tolerability, and antidepressant effi- cacy (NCT02481245). Vitamin B12 Vitamin B12, or cobalamin, is a cofactor for methionine synthe- sis, required for DNA and myelin synthesis and maintenance Conclusion of neuronal integrity as well as neurotransmitter regulation. Vitamin B12 deficiency is a common but often under-recognized The study of neuroinflammation, neurodegeneration, and mito- chondrial function has contributed to the understanding of condition causing neurologic, cognitive, psychiatric, and mood symptoms (Lindenbaum et al., 1988; Issac et al., 2015). Further, BD’s pathophysiology and led to the exploration of agents tar - geting these pathways. While some negative effects have been deficiencies of B12, folate, or B6 can lead to macrocytic or per - nicious anemia with symptoms of fatigue, psychomotor, cogni- reported, compounds tested to date have been well-tolerated in the existing clinical data. Future directions include combinations tive, and mood deficits (Selhub et al., 2009). In an RCT in elderly participants with depressive symptoms, long-term daily sup- of compounds targeting multiple mitochondrial pathways with potentially synergistic effects. Additionally, combinations with plementation with folic acid and vitamin B12 improved cogni- tive functioning, particularly immediate and delayed memory antioxidant or antiinflammatory agents could be feasible next steps to achieve better outcomes due to the role of inflammation performance (Walker et al., 2012). More relevant to BD, there is Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/550/4955527 by Ed 'DeepDyve' Gillespie user on 21 June 2018 562 | International Journal of Neuropsychopharmacology, 2018 and oxidative stress in generation and maintenance of mito- Anglin RE, Samaan Z, Walter SD, McDonald SD (2013) Vitamin D chondrial dysfunction (Rodriguez et al., 2007; Tarnopolsky, 2008). deficiency and depression in adults: systematic review and Identification of novel candidate mitochondrial modulators as meta-analysis. Br J Psychiatry 202:100–107. well as rigorous and well-powered clinical trials are needed to Aoyama T, Peters JM, Iritani N, Nakajima T, Furihata K, Hashimoto explore this potential therapeutic strategy. T, Gonzalez FJ (1998) Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (pparalpha). J Biol Chem Acknowledgments 273:5678–5684. M.B. is supported by a NHMRC Senior Principal Research Arrigoni O, De Tullio MC (2002) Ascorbic acid: much more than just an antioxidant. Biochim Biophys Acta 1569:1–9. Fellowship (GNT1059660). Aureli T, Di Cocco ME, Puccetti C, Ricciolini R, Scalibastri M, Miccheli A, Manetti C, Conti F (1998) Acetyl-L-carnitine mod- Statement of Interest ulates glucose metabolism and stimulates glycogen synthe- sis in rat brain. Brain Res 796:75–81. 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International Journal of Neuropsychopharmacology – Oxford University Press
Published: Mar 27, 2018
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