Patterns of pharmacotherapy for bipolar disorder: A GBC survey.

OBJECTIVES: To understand treatment practices for bipolar disorders (BD), this study leveraged the Global Bipolar Cohort collaborative network to investigate pharmacotherapeutic treatment patterns in multiple cohorts of well-characterized individuals with BD in North America, Europe, and Australia. METHODS: Data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities were provided from each participating cohort. Individual site and regional pooled proportional meta-analyses with generalized linear mixed methods were conducted to identify prescription patterns. RESULTS: This study included 10,351 individuals from North America (n = 3985), Europe (n = 3822), and Australia (n = 2544). Overall, participants were predominantly female (60%) with BD-I (60%; vs. BD-II = 33%). Cross-sectionally, mood-stabilizing anticonvulsants (44%), second-generation antipsychotics (42%), and antidepressants (38%) were the most prescribed medications. Lithium was prescribed in 29% of patients, primarily in the Australian (31%) and European (36%) cohorts. First-generation antipsychotics were prescribed in 24% of the European versus 1% in the North American cohort. Antidepressant prescription rates were higher in BD-II (47%) compared to BD-I (35%). Major limitations were significant differences among cohorts based on inclusion/exclusion criteria, data source, and time/year of enrollment into cohort. CONCLUSIONS: Mood-stabilizing anticonvulsants, second-generation antipsychotics, and antidepressants were the most prescribed medications suggesting prescription patterns that are not necessarily guideline concordant. Significant differences exist in the prescription practices across different geographic regions, especially the underutilization of lithium in the North American cohorts and the higher utilization of first-generation antipsychotics in the European cohorts. There is a need to conduct future longitudinal studies to further explore these differences and their impact on outcomes, and to inform and implement evidence-based guidelines to help improve treatment practices in BD.

Inflammatory markers, brain-derived neurotrophic factor, and the symptomatic course of adolescent bipolar disorder: A prospective repeated-measures study.

BACKGROUND: Numerous studies have found elevated pro-inflammatory markers and reduced brain-derived neurotrophic factor (BDNF) during symptomatic episodes of bipolar disorder (BD) in adults. There is a paucity of research examining these markers in youth with BD, or longitudinally in any BD age group. METHODS: 79 adolescents, ages 13-19 years, were enrolled, including 43 symptomatic adolescents with BD and 36 age-matched healthy controls (HC). Blood samples were collected from all participants at intake, and repeatedly from BD participants at pre-specified intervals over the course of two years. Serum was assayed for levels of pro-inflammatory markers (c-reactive protein [CRP], interleukin [IL]-6, tumor necrosis factor alpha [TNF-α]), BDNF and the anti-inflammatory marker, IL-10. Week-by-week severity of mood symptoms was assessed using semi-structured interviews. RESULTS: Adolescents with BD provided an average of 4.6 blood samples, on average every 5.0 months. During the most severe symptomatic interval (i.e., highest sum of mood symptom scores) among BD adolescents, levels of CRP (p = 0.01) and pro- to anti-inflammatory ratios (CRP/IL-10; p < 0.001 and IL-6/IL-10; p = 0.046) were significantly greater, and IL-10 levels (p = 0.004) were significantly lower, vs. HC. There were no differences between BD and HC in IL-6, TNF-α or BDNF. Within BD participants, higher BDNF (p = 0.01) and IL-10 levels (p = 0.001) significantly predicted greater burden of mood symptoms over the subsequent epoch. Moreover, higher CRP levels (p = 0.009) at intake predicted greater time to recovery from the index symptomatic episode. CONCLUSIONS: In the first repeated-measures study on this topic in adolescents with BD, we found evidence that CRP, an inexpensive and ubiquitous blood test, may be useful in predicting the prospective course of BD symptoms. Future larger studies are warranted.

Strategies and foundations for scientific discovery in longitudinal studies of bipolar disorder.

Bipolar disorder (BD) is a complex and dynamic condition with a typical onset in late adolescence or early adulthood followed by an episodic course with intervening periods of subthreshold symptoms or euthymia. It is complicated by the accumulation of comorbid medical and psychiatric disorders. The etiology of BD remains unknown and no reliable biological markers have yet been identified. This is likely due to lack of comprehensive ontological framework and, most importantly, the fact that most studies have been based on small nonrepresentative clinical samples with cross-sectional designs. We propose to establish large, global longitudinal cohorts of BD studied consistently in a multidimensional and multidisciplinary manner to determine etiology and help improve treatment. Herein we propose collection of a broad range of data that reflect the heterogenic phenotypic manifestations of BD that include dimensional and categorical measures of mood, neurocognitive, personality, behavior, sleep and circadian, life-story, and outcomes domains. In combination with genetic and biological information such an approach promotes the integrating and harmonizing of data within and across current ontology systems while supporting a paradigm shift that will facilitate discovery and become the basis for novel hypotheses.

Exercise priming with transcranial direct current stimulation: a study protocol for a randomized, parallel-design, sham-controlled trial in mild cognitive impairment and Alzheimer's disease.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive type of brain stimulation that uses electrical currents to modulate neuronal activity. A small number of studies have investigated the effects of tDCS on cognition in patients with Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD), and have demonstrated variable effects. Emerging evidence suggests that tDCS is most effective when applied to active brain circuits. Aerobic exercise is known to increase cortical excitability and improve brain network connectivity. Exercise may therefore be an effective, yet previously unexplored primer for tDCS to improve cognition in MCI and mild AD. METHODS: Participants with MCI or AD will be randomized to receive 10 sessions over 2 weeks of either exercise primed tDCS, exercise primed sham tDCS, or tDCS alone in a blinded, parallel-design trial. Those randomized to an exercise intervention will receive individualized 30-min aerobic exercise prescriptions to achieve a moderate-intensity dosage, equivalent to the ventilatory anaerobic threshold determined by cardiopulmonary assessment, to sufficiently increase cortical excitability. The tDCS protocol consists of 20 min sessions at 2 mA, 5 times per week for 2 weeks applied through 35 cm2 bitemporal electrodes. Our primary aim is to assess the efficacy of exercise primed tDCS for improving global cognition using the Montreal Cognitive Assessment (MoCA). Our secondary aims are to evaluate the efficacy of exercise primed tDCS for improving specific cognitive domains using various cognitive tests (n-back, Word Recall and Word Recognition Tasks from the Alzheimer's Disease Assessment Scale-Cognitive subscale) and neuropsychiatric symptoms (Neuropsychiatric Inventory). We will also explore whether exercise primed tDCS is associated with an increase in markers of neurogenesis, oxidative stress and angiogenesis, and if changes in these markers are correlated with cognitive improvement. DISCUSSION: We describe a novel clinical trial to investigate the effects of exercise priming before tDCS in patients with MCI or mild AD. This proof-of-concept study may identify a previously unexplored, non-invasive, non-pharmacological combination intervention that improves cognitive symptoms in patients. Findings from this study may also identify potential mechanistic actions of tDCS in MCI and mild AD. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03670615 . Registered on September 13, 2018.

Characterizing the NLRP3 Inflammasome in Mood Disorders: Overview, Technical Development, and Measures of Peripheral Activation in Adolescent Patients.

The NOD-, LRR-, and pyrin-domain-containing protein 3 (NLRP3) inflammasome is a node of intracellular stress pathways and a druggable target which integrates mitochondrial stress and inflammatory cascades. While a body of evidence suggests the involvement of the NLRP3 inflammasome in numerous diseases, a lack of reliable measurement techniques highlights the need for a robust assay using small quantities of biological samples. We present a literature overview on peripheral activation of the NLRP3 inflammasome in mood disorders, then outline a process to develop and validate a robust assay to measure baseline and activated intracellular levels of "apoptosis-associated speck-like protein containing a CARD" (ASC) as a key component of an inflammatory profile in peripheral blood mononuclear cells (PBMC). A consistent association between high NLRP3 mRNA levels and relevant cytokines was seen in the literature. Using our method to measure ASC, stimulation of PBMC with lipopolysaccharide and nigericin or adenosine triphosphate resulted in microscopic identification of intracellular ASC specks, as well as interleukin 1 (IL-1) beta and caspase-1 p10 in the periphery. This was abolished by dose-dependent pre-treatment with 100 nM MCC950. We also report the use of this technique in a small pilot sample from patients with bipolar disorder and depressive disorders. The results show that levels of intracellular ASC and IL-1 beta are sensitive to change upon activation and maintained over time, which may be used to improve the detection of NLRP3 activation and guide personalized therapeutic strategy in the treatment of patients.

Agitation, Oxidative Stress, and Cytokines in Alzheimer Disease: Biomarker Analyses From a Clinical Trial With Nabilone for Agitation.

The endocannabinoid system has been a target of interest for agitation in Alzheimer disease (AD) because of potential behavioral effects and its potential impact on mechanisms implicated in AD such as oxidative stress (OS) and neuroinflammation. We explored whether serum markers of OS and neuroinflammation were associated with response to the cannabinoid nabilone in agitated patients with AD (N = 38). All participants were enrolled in a 14-week, double-blind, cross-over trial comparing nabilone to placebo (6 weeks each) with a 1-week washout between phases. Samples were collected at the start and end of each phase. The cross-sectional relationship agitation (Cohen Mansfield Agitation Inventory) and OS and inflammatory markers were investigated to select markers of interest. Significant markers were then explored for their relationship with response. The OS marker, 4-hydroxynonenal (4-HNE; F1, 35 = 6.41, P = .016), and the proinflammatory cytokine, tumor necrosis factor-α (TNF-α; F1, 29 = 3.97, P = .06), were associated with agitation severity, and TNF-α remained significantly associated (F2, 25 = 3.69, P = .04) after adjustment for cognition. In the placebo phase, lower baseline 4-HNE was associated with decreases in agitation severity only (b = 0.01, P = .01), while lower baseline TNF-α was associated with decreases in agitation severity in the nabilone phase only (b = 1.14, P = .045). Changes in 4-HNE were not associated with changes in agitation severity in either phase. In the nabilone phase, lower baseline TNF-α was associated with decreases in agitation severity (b = 1.14, P = .045), and decreases in TNF-α were associated with decreases in agitation severity (b = 1.12, P = .006). These findings suggest that OS and neuroinflammation may be associated with agitation severity, while nabilone may have anti-inflammatory effects.

Glutathione, the Major Redox Regulator, in the Prefrontal Cortex of Individuals at Clinical High Risk for Psychosis.

Introduction: Oxidative stress and glutathione dysregulation have been implicated in the etiology of schizophrenia. To date, most in vivo studies have investigated alterations in cerebral glutathione levels in patients in which the disorder is already established; however, whether oxidative stress actually predates the onset of psychosis remains unknown. In the current study, we investigated cerebral glutathione levels of antipsychotic-naïve individuals at clinical high risk for psychosis. As exploratory analyses, we also investigated the associations between cerebral glutathione levels and peripheral glutathione peroxidase activity and clinical and neuropsychological measures. Methods: Glutathione levels were measured in the medial prefrontal cortex of 30 clinical high risk (n=26 antipsychotic naïve) and 26 healthy volunteers using 3T proton magnetic resonance spectroscopy. Each participant was assessed for glutathione peroxidase activity in plasma and genotyped for the glutamate cysteine ligase catalytic subunit polymorphism. Results: No significant differences were observed in glutathione levels between clinical high risk and healthy volunteers in the medial prefrontal cortex (F(1,54)=0.001, P =0.98). There were no significant correlations between cerebral glutathione levels and clinical and neuropsychological measures. Similarly, no significant differences were found in peripheral glutathione peroxidase activity between clinical high risk and healthy volunteers (F(1,37)=0.15, P =0.70). However, in clinical high risk, we observed a significant effect of lifetime history of cannabis use on glutathione peroxidase activity (F(1,23)=7.41, P =0.01). Discussion: The lack of significant differences between antipsychotic naïve clinical high risk and healthy volunteers suggests that alterations in glutathione levels in medial prefrontal cortex are not present in the clinical high risk state.

Atorvastatin in the treatment of Lithium-induced nephrogenic diabetes insipidus: the protocol of a randomized controlled trial.

BACKGROUND: Lithium is the gold-standard treatment for bipolar disorder, is highly effective in treating major depressive disorder, and has anti-suicidal properties. However, clinicians are increasingly avoiding lithium largely due to fears of renal toxicity. Nephrogenic Diabetes Insipidus (NDI) occurs in 15-20% of lithium users and predicts a 2-3 times increased risk of chronic kidney disease (CKD). We recently found that use of statins is associated with lower NDI risk in a cross-sectional study. In this current paper, we describe the methodology of a randomized controlled trial (RCT) to treat lithium-induced NDI using atorvastatin. METHODS: We will conduct a 12-week, double-blind placebo-controlled RCT of atorvastatin for lithium-induced NDI at McGill University, Montreal, Canada. We will recruit 60 current lithium users, aged 18-85, who have indicators of NDI, which we defined as urine osmolality (UOsm) < 600 mOsm/kg after 10-h fluid restriction. We will randomize patients to atorvastatin (20 mg/day) or placebo for 12 weeks. We will examine whether this improves measures of NDI: UOsm and aquaporin (AQP2) excretion at 12-week follow-up, adjusted for baseline. RESULTS: Not applicable. CONCLUSION: The aim of this clinical trial is to provide preliminary data about the efficacy of atorvastatin in treating NDI. If successful, lithium could theoretically be used more safely in patients with a reduced subsequent risk of CKD, hypernatremia, and acute kidney injury (AKI). If future definitive trials confirm this, this could potentially allow more patients to benefit from lithium, while minimizing renal risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT02967653 . Registered in February 2017.

Lactate in bipolar disorder: A systematic review and meta-analysis.

Bipolar disorder (BD) is a debilitating mood disorder with no specific biological marker. No novel treatment has been developed specifically for BD in the last several decades. Although the pathophysiology of BD remains unclear, there is strong evidence in the literature supporting the role of mitochondrial dysfunction in BD. In this systematic review, we identified and investigated 12 studies that measure lactate, which is a direct marker for mitochondrial dysfunction, in BD patients and healthy controls. Six studies measured lactate levels in the brain through proton echo-planar spectroscopy or magnetic resonance spectroscopy and five of these studies reported significantly elevated lactate levels in patients with BD. Two studies reporting cerebrospinal fluid lactate levels also found significantly elevated lactate in BD compared to healthy controls. Two other studies that reported peripheral lactate levels did not demonstrate significant findings. The meta-analysis, using standardized means and a random-effect model for five studies that measured brain lactate levels, corroborated the findings of the systematic review. Although the meta-analysis had a nearly significant overall effect (Z = 1.97, P = 0.05), high statistical heterogeneity (I2 = 86%) and possible publication bias suggest that the results should be interpreted with caution. To validate lactate abnormalities in BD, further studies should be carried out, including larger sample sizes, not excluding female patients, and using standardized methodologies. Peripheral lactate levels and other bioenergetic markers should be thoroughly studied to better understand the role of mitochondrial dysfunction in BD and to help develop more objective diagnostic tools.

Oxidative stress predicts depressive symptom changes with omega-3 fatty acid treatment in coronary artery disease patients.

BACKGROUND: Antidepressant efficacy of omega-3 polyunsaturated fatty acid (n-3 PUFA) treatment in coronary artery disease (CAD) patients remains unpredictable. N-3 PUFA can mitigate oxidative stress, which is common in CAD and may contribute to depressive symptoms. This study investigated whether greater pre-treatment oxidative stress, measured by the ratios of late-stage lipid peroxidation markers (malondialdehyde [MDA], 4-hydroxy-2-nonenal [4-HNE], and 8-isoprostane [8-ISO]) to an early-stage marker (lipid hydroperoxides [LPH]), predicted n-3 PUFA antidepressant benefits in CAD. METHODS: This was a secondary analysis of CAROTID (CAD Randomized Omega-3 Trial in Depression, NCT00981383). Patient demographics and medical characteristics were collected. Depressive symptoms were measured using the 17-item Hamilton Depression Rating Scale (HAM-D). Patients were then randomized to receive either 1.9g/day n-3 PUFA or placebo for 12weeks, after which HAM-D scores were reassessed. Baseline LPH, 4-HNE, 8-ISO, MDA and n-3 PUFA concentrations were analysed from fasting blood. RESULTS: Seventy-nine patients (age=61.1±8.5, 76% male, HAM-D=7.5±6.1) were included (n=45 placebo, n=34 n-3 PUFA). In the n-3 PUFA group, higher baseline ratios of MDA/LPH (primary analysis: F1,33=6.20, beta=-0.35, p=0.018), 4-HNE/LPH (exploratory analysis: F1,33=5.35, beta=-0.32, p=0.027), and 8-ISO/LPH (exploratory analysis: F1,33=6.10, beta=-0.33, p=0.019), indicating higher oxidative stress, were associated with greater depressive symptom improvement. In each model, higher baseline EPA+DHA concentrations independently predicted depressive symptom improvement with n-3 PUFA (MDA/LPH: F1,33=11.05, p=0.002; 4-HNE/LPH: F1,33=11.36, p=0.002; 8-ISO/LPH: F1,33=13.15, p=0.001). No associations were observed in the placebo group. CONCLUSIONS: n-3 PUFA may be more likely to improve depressive symptoms in CAD patients with pre-treatment evidence of oxidative stress.

Neuroinflammation and Oxidative Stress in Psychosis and Psychosis Risk.

Although our understanding of psychotic disorders has advanced substantially in the past few decades, very little has changed in the standard of care for these illnesses since the development of atypical anti-psychotics in the 1990s. Here, we integrate new insights into the pathophysiology with the increasing interest in early detection and prevention. First, we explore the role of N-methyl-d-aspartate receptors in a subpopulation of cortical parvalbumin-containing interneurons (PVIs). Postmortem and preclinical data has implicated these neurons in the positive and negative symptoms, as well as the cognitive dysfunction present in schizophrenia. These neurons also appear to be sensitive to inflammation and oxidative stress during the perinatal and peripubertal periods, which may be mediated in large part by aberrant synaptic pruning. After exploring some of the molecular mechanisms through which neuroinflammation and oxidative stress are thought to exert their effects, we highlight the progress that has been made in identifying psychosis prior to onset through the identification of individuals at clinical high risk for psychosis (CHR). By combining our understanding of psychosis pathogenesis with the increasing characterization of endophenotypes that precede frank psychosis, it may be possible to identify patients before they present with psychosis and intervene to reduce the burden of the disease to both patients and families.

Dentate gyrus-cornu ammonis (CA) 4 volume is decreased and associated with depressive episodes and lipid peroxidation in bipolar II disorder: Longitudinal and cross-sectional analyses.

OBJECTIVES: Reduced dentate gyrus volume and increased oxidative stress have emerged as potential pathophysiological mechanisms in bipolar disorder. However, the relationship between dentate gyrus volume and peripheral oxidative stress markers remains unknown. Here, we examined dentate gyrus-cornu ammonis (CA) 4 volume longitudinally in patients with bipolar II disorder (BD-II) and healthy controls and investigated whether BD-II is associated with elevated peripheral levels of oxidative stress. METHODS: We acquired high-resolution structural 3T-magnetic resonance imaging (MRI) images and quantified hippocampal subfield volumes using an automated segmentation algorithm in individuals with BD-II (n=29) and controls (n=33). The participants were scanned twice, at study inclusion and on average 2.4 years later. In addition, we measured peripheral levels of two lipid peroxidation markers (4-hydroxy-2-nonenal [4-HNE] and lipid hydroperoxides [LPH]). RESULTS: First, we demonstrated that the automated hippocampal subfield segmentation technique employed in this work reliably measured dentate gyrus-CA4 volume. Second, we found a decreased left dentate gyrus-CA4 volume in patients and that a larger number of depressive episodes between T1 and T2 predicted greater volume decline. Finally, we showed that 4-HNE was elevated in BD-II and that 4-HNE was negatively associated with left and right dentate gyrus-CA4 volumes in patients. CONCLUSIONS: These results are consistent with a role for the dentate gyrus in the pathophysiology of bipolar disorder and suggest that depressive episodes and elevated oxidative stress might contribute to hippocampal volume decreases. In addition, these findings provide further support for the hypothesis that peripheral lipid peroxidation markers may reflect brain alterations in bipolar disorders.

Decreased Brain-Derived Neurotrophic Factor in Older Adults with Bipolar Disorder.

OBJECTIVES: Decreased levels of brain derived neurotrophic factor (BDNF) have been found in adult patients with bipolar disorder (BD) compared with a comparison group, yet there are no data specifically examining this in geriatric patients. The objective of this study was to examine whether euthymic late-life BD patients have lower BDNF levels than healthy comparators. DESIGN: Cross-sectional study. SETTING: Clinics at the University of Pittsburgh and the Centre for Addiction and Mental Health (Toronto). PARTICIPANTS: Older patients with BD (age ≥50 years, N = 118) and similarly aged healthy comparators (N = 76). There were both BD type I (N = 91) and type II (N = 27) patients. MEASUREMENTS: Serum BDNF levels were assessed in BD patients and healthy comparators. RESULTS: We found lower levels of BDNF in patients with BD than in healthy comparators (9.0 ± 6.2 versus 12.3 ± 8.9 pg/µg, t(192) = -3.01, p = 0.002), which remained even after controlling for age, sex, lithium use, and site (F(1,176) = 4.32, p = 0.039). This decrease was found specifically in patients with BD type I (8.0 ± 5.5 versus 12.3 ± 8.9 pg/µg, t(165) = 3.7, Bonferroni p < 0.001), but not type II (12.0 ± 7.5 versus 12.3 ± 8.9 pg/µg, t(101) = 0.14, Bonferroni p = 1.0). CONCLUSIONS: Older patients with BD have lower serum levels of BDNF compared with similarly aged comparators. These effects appear to be specific to patients with BD type I. Future studies are needed to investigate the impact of reduced BDNF levels on cognition, mood, and other aspects of BD throughout the life course.

Discovering biomarkers for antidepressant response: protocol from the Canadian biomarker integration network in depression (CAN-BIND) and clinical characteristics of the first patient cohort.

BACKGROUND: Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Identification of clinical and biological markers ("biomarkers") of treatment response could personalize clinical decisions and lead to better outcomes. This paper describes the aims, design, and methods of a discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). The CAN-BIND research program investigates and identifies biomarkers that help to predict outcomes in patients with MDD treated with antidepressant medication. The primary objective of this initial study (known as CAN-BIND-1) is to identify individual and integrated neuroimaging, electrophysiological, molecular, and clinical predictors of response to sequential antidepressant monotherapy and adjunctive therapy in MDD. METHODS: CAN-BIND-1 is a multisite initiative involving 6 academic health centres working collaboratively with other universities and research centres. In the 16-week protocol, patients with MDD are treated with a first-line antidepressant (escitalopram 10-20 mg/d) that, if clinically warranted after eight weeks, is augmented with an evidence-based, add-on medication (aripiprazole 2-10 mg/d). Comprehensive datasets are obtained using clinical rating scales; behavioural, dimensional, and functioning/quality of life measures; neurocognitive testing; genomic, genetic, and proteomic profiling from blood samples; combined structural and functional magnetic resonance imaging; and electroencephalography. De-identified data from all sites are aggregated within a secure neuroinformatics platform for data integration, management, storage, and analyses. Statistical analyses will include multivariate and machine-learning techniques to identify predictors, moderators, and mediators of treatment response. DISCUSSION: From June 2013 to February 2015, a cohort of 134 participants (85 outpatients with MDD and 49 healthy participants) has been evaluated at baseline. The clinical characteristics of this cohort are similar to other studies of MDD. Recruitment at all sites is ongoing to a target sample of 290 participants. CAN-BIND will identify biomarkers of treatment response in MDD through extensive clinical, molecular, and imaging assessments, in order to improve treatment practice and clinical outcomes. It will also create an innovative, robust platform and database for future research. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01655706 . Registered July 27, 2012.

Antioxidant treatments for schizophrenia.

BACKGROUND: There is accumulating evidence that progressive changes in brain structure and function take place as schizophrenia unfolds. Among many possible candidates, oxidative stress may be one of the mediators of neuroprogression, grey matter loss and subsequent cognitive and functional impairment. Antioxidants are exogenous or endogenous molecules that mitigate any form of oxidative stress or its consequences. They may act from directly scavenging free radicals to increasing anti-oxidative defences. There is evidence that current treatments impact oxidative pathways and may to some extent reverse pro-oxidative states in schizophrenia. The existing literature, however, indicates that these treatments do not fully restore the deficits in antioxidant levels or restore levels of oxidants in schizophrenia. As such, there has been interest in developing interventions aimed at restoring this oxidative balance beyond the benefits of antipsychotics in this direction. If antioxidants are to have a place in the treatment of this serious condition, the relevant and up-to-date information should be available to clinicians and investigators. OBJECTIVES: To evaluate the effect of antioxidants as add-on treatments to standard antipsychotic medication for improving acute psychotic episodes and core symptoms, and preventing relapse in people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There are no language, time, document type, or publication status limitations for inclusion of records in the register. We ran this search in November 2010, and again on 8 January 2015. We also inspected references of all identified studies for further trials and contacted authors of trials for additional information. SELECTION CRITERIA: We included reports if they were randomised controlled trials (RCTs) involving people with schizophrenia who had been allocated to either a substance with antioxidant potential or to a placebo as an adjunct to standard antipsychotic treatment. DATA COLLECTION AND ANALYSIS: We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE. MAIN RESULTS: The review includes 22 RCTs of varying quality and sample size studying Ginkgo biloba, N-acetyl cysteine (NAC), allopurinol, dehydroepiandrosterone (DHEA), vitamin C, vitamin E or selegiline. Median follow-up was eight weeks. Only three studies including a minority of the participants reported our a priori selected primary outcome of clinically important response. Short-term data for this outcome (measured as at least 20% improvement in scores on Positive and Negative Syndrome Scale (PANSS)) were similar (3 RCTs, n = 229, RR 0.77, 95% CI 0.53 to 1.12, low quality evidence). Studies usually reported only endpoint psychopathology rating scale scores. Psychotic symptoms were lower in those using an adjunctive antioxidant according to the PANSS ( 7 RCTS, n = 584, MD -6.00, 95% CI -10.35 to -1.65, very low quality evidence) and the Brief Psychiatric Rating Scale (BPRS) (8 RCTS, n = 843, MD -3.20, 95% CI -5.63 to -0.78, low quality evidence). There was no overall short-term difference in leaving the study early (16 RCTs, n = 1584, RR 0.73, 95% CI 0.48 to 1.11, moderate quality evidence), or in general functioning (2 RCTs, n = 52, MD -1.11, 95% CI -8.07 to 5.86, low quality evidence). Adverse events were generally poorly reported. Three studies reported useable data for 'any serious adverse effect', results were equivocal (3 RCTs, n = 234, RR 0.65, 95% CI 0.19 to 2.27, low quality evidence). No evidence was available for relapse, quality of life or service use. AUTHORS' CONCLUSIONS: Although 22 trials could be included in this review, the evidence provided is limited and mostly not relevant to clinicians or consumers. Overall, although there was low risk of attrition and selective data reporting bias within the trials, the trials themselves were not adequately powered and need more substantial follow-up periods. There is a need for larger trials with longer periods of follow-up to be conducted. Outcomes should be meaningful for those with schizophrenia, and include measures of improvement and relapse (not just rating scale scores), functioning and quality of life and acceptability and, importantly, safety data.

Mitochondrial dysfunction in schizophrenia: an evolutionary perspective.

Schizophrenia (SCZ) is a severe psychiatric illness with a lifetime prevalence of 0.4 %. A disturbance of energy metabolism has been suggested as part of the etiopathogenesis of the disorder. Several lines of evidence have proposed a connection between etiopathogenesis of SCZ and human brain evolution, which was characterized by an increase in the energy requirement, demanding a co-evolution of the mitochondrial system. Mitochondria are key players in brain energy homeostasis and multiple lines of evidence suggest that the system is disrupted in SCZ. In this review, we will describe the current knowledge on pathways/system involved in the human brain evolution as well as the main theories regarding the evolutionary origin of SCZ. We will furthermore discuss the role of mitochondria in the context of brain energy metabolism and its role in the etiopathogenesis of SCZ. Understanding SCZ in the context of human brain evolution opens a new perspective to elucidate pathophysiological mechanisms involved in the origin and/or portions of the complex symptomatology of this severe mental disorder.

The neurobiology of bipolar disorder: identifying targets for specific agents and synergies for combination treatment.

Bipolar disorder (BD) is a chronic psychiatric illness described by severe changes in mood. Extensive research has been carried out to understand the aetiology and pathophysiology of BD. Several hypotheses have been postulated, including alteration in genetic factors, protein expression, calcium signalling, neuropathological alteration, mitochondrial dysfunction and oxidative stress in BD. In the following paper, we will attempt to integrate these data in a manner which is to understand targets of treatment and how they may be, in particular, relevant to combination treatment. In summary, the data suggested that BD might be associated with neuronal and glial cellular impairment in specific brain areas, including the prefrontal cortex. From molecular and genetics: (1) alterations in dopaminergic system, through catechol-O-aminotransferase; (2) decreased expression and polymorphism on brain-derived neurotrophic factor; (3) alterations cyclic-AMP responsive element binding; (4) dysregulation of calcium signalling, including genome-wide finding for voltage-dependent calcium channel α-1 subunit are relevant findings in BD. Future studies are now necessary to understand how these molecular pathways interact and their connection to the complex clinical manifestations observed in BD.

Decreased global methylation in patients with bipolar disorder who respond to lithium.

Mitochondrial dysfunction, oxidative stress, and alterations in DNA methylation, are all associated with the pathophysiology of bipolar disorder (BD). We therefore studied the relationship between oxidative stress and DNA methylation in patients with BD with an excellent response to lithium treatment, their affected and unaffected relatives and healthy controls. Transformed lymphoblasts were cultured in the presence or absence of lithium chloride (0.75 mM). DNA and proteins were extracted from the cells to determine levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), 5-methylcytosine (5-mc), mitochondrial complex I and glutathione peroxidase (GPx) activities. Methylation was decreased in BD subjects and their relatives compared to controls and remained so after lithium treatment in BD subjects but not in their relatives. 8-OHdG levels and complex I activity did not differ between groups before and after lithium treatment. Finally, relatives of patients showed increased GPx activity before and after lithium treatment, which negatively correlated with 5-mc levels. Changes in global methylation may be specific for BD and lithium may be involved in glutathione regulation. The present study supports the importance of DNA methylation to the pathophysiology of BD and the therapeutic potential of antioxidants in this illness.

Acute Cannabis Administration Transiently Reduces Mitochondrial DNA in Young Adults: Findings from a Secondary Analysis of a Double-Blind, Placebo-Controlled, Randomized Clinical Trial.

Background: Cannabis is one of the world's most commonly used substances; however, many questions remain unanswered as to how cannabis impacts the body. Recently, there has been a resurgence of research into the effects of plant-derived cannabinoids on mitochondrial health. In particular, a number of studies implicate mitochondrial-Δ9-tetrahydrocannabinol (Δ9-THC) interactions with altered memory, metabolism, and catalepsy in mice. Although the research in this field is expanding rapidly, there is little known about the effects of cannabis on mitochondria health in human subjects either in acute or chronic term use. Methods: Blood samples were obtained from a double-blind, placebo-controlled, parallel-group randomized clinical trial in which adults who regularly use cannabis (1-4 days/week) aged 19-25 years were randomized 2:1 to receive either an active (12.5% Δ9-THC) cigarette or placebo (<0.01% Δ9-THC) cigarette containing 750 mg of cannabis before driving simulator testing. DNA was extracted from whole blood using commercial spin columns, followed by measurement of mt-ND1, mt-ND4, and ß2M using quantitative polymerase chain reaction. One-way repeated measures analysis of variance (ANOVA) followed by Dunnett's multiple comparisons test was used to observe changes in mitochondrial DNA (mtDNA) copy number over time. A two-tailed Pearsons R test was used to assess correlations between mtDNA copy number and cannabinoid levels (Δ9-THC and metabolites) in blood. Results: We found that exposure to active cannabis containing Δ9-THC, as opposed to placebo, was associated with an acute reduction in mitochondrial DNA copy number in whole blood at 15 min and 1 h after smoking. The observed decrease in mtDNA copy number negatively correlated with blood concentrations of 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-Nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH), the two primary metabolites of Δ9-THC, but not Δ9-THC itself. Further, the negative correlation between 11-OH THC and THC-COOH concentrations and mtDNA copy number was found in only a subgroup of participants who use cannabis infrequently, suggesting a tolerance effect. Conclusions: These results illuminate mitochondrial alterations attributed to Δ9-THC consumption, which may be mediated by metabolites. These results appear to suggest stronger effects in individuals who consume cannabis less frequently, suggesting some form of tolerance to the effects of Δ9-THC and its metabolites on mtDNA content in whole blood. Keywords: Mitochondria; mtDNA; cannabis; THC; THC metabolites; blood; THC-COOH; 11-OH-THC.

Pilot study of circulating cell-free mitochondrial DNA in relation to brain structure in youth bipolar disorder.

BACKGROUND: Mitochondrial dysfunction is implicated in the neuropathology of bipolar disorder (BD). Higher circulating cell-free mitochondrial DNA (ccf-mtDNA), generally reflecting poorer mitochondrial health, has been associated with greater symptoms severity in BD. The current study examines the association of serum ccf-mtDNA and brain structure in relation to youth BD. We hypothesized that higher ccf-mtDNA will be associated with measures of lower brain structure, particularly in the BD group. METHODS: Participants included 40 youth (BD, n = 19; Control group [CG], n = 21; aged 13-20 years). Serum ccf-mtDNA levels were assayed. T1-weighted brain images were acquired using 3T-MRI. Region of interest (ROI) analyses examined prefrontal cortex (PFC) and whole brain gray matter, alongside exploratory vertex-wise analyses. Analyses examined ccf-mtDNA main-effects and ccf-mtDNA-by-diagnosis interaction effects controlling for age, sex, and intracranial volume. RESULTS: There was no significant difference in ccf-mtDNA levels between BD and CG. In ROI analyses, higher ccf-mtDNA was associated with higher PFC surface area (SA) (ß = 0.32 p < 0.001) and PFC volume (ß = 0.32 p = 0.002) in the overall sample. In stratified analyses, higher ccf-mtDNA was associated with higher PFC SA within both subgroups (BD: ß = 0.39 p = 0.02; CG: ß = 0.24 p = 0.045). Higher ccf-mtDNA was associated with higher PFC volume within the BD group (ß = 0.39 p = 0.046). In vertex-wise analyses, higher ccf-mtDNA was associated with higher SA and volume in frontal clusters within the overall sample and within the BD group. There were significant ccf-mtDNA-by-diagnosis interactions in three frontal and parietal clusters, whereby higher ccf-mtDNA was associated with higher neurostructural metrics in the BD group but lower neurostructural metrics in CG. CONCLUSIONS: Contrasting our hypothesis, higher ccf-mtDNA was consistently associated with higher, rather than lower, regional neuralstructural metrics among youth with BD. While this finding may reflect a compensatory mechanism, future repeated-measures prospective studies evaluating the inter-relationship among ccf-mtDNA, mood, and brain structure across developmental epochs and illness stages are warranted.