Mitochondrial health index correlates with plasma circulating cell-free mitochondrial DNA in bipolar disorder.

Although mitochondrial dysfunction is known to play an essential role in the pathophysiology of bipolar disorder (BD), there is a glaring gap in our understanding of how mitochondrial dysfunction can modulate clinical phenotypes. An emerging paradigm suggests mitochondria play an important non-energetic role in adaptation to stress, impacting cellular resilience and acting as a source of systemic allostatic load. Known as mitochondrial allostatic load, this (phenomenon) occurs when mitochondria are unable to recalibrate and maintain cell homeostasis. This study aimed to evaluate the composite mitochondrial health index (MHI) in BD subjects and non-psychiatry controls. We will also explore whether lower MIH will be related to higher cell-free mtDNA (ccf-mtDNA) levels and poor clinical outcomes. In this study, 14 BD-I patients and 16 age- and sex-matched non-psychiatry controls were enrolled. Peripheral blood mononuclear cells (PBMCs) were used to measure the enzymatic activities of citrate synthase and complexes I, II, and IV and mtDNA copy number. Ccf-mtDNA was evaluated by qPCR in plasma. Mitochondrial quality control (MQC) proteins were evaluated by western blotting. After adjusting for confounding variables, such as age, sex, body mass index (BMI), and smoking status, patients with BD presented lower MHI compared to non-psychiatry controls, as well as higher ccf-mtDNA levels that negatively correlated with MHI. Because the MQC network is essential to maintain mitochondrial health, MHI and ccf-mtDNA were also examined in relation to several MQC-related proteins, such as Fis-1, Opa-1, and LC3. Our results showed that MHI correlated negatively with Fis-1 and positively with Opa-1 and LC3. Accordingly, ccf-mtDNA had a positive correlation with Fis-1 and a negative correlation with Opa-1 and LC3. Furthermore, we found a noteworthy inverse correlation between illness severity and MHI, with lower MHI and higher ccf-mtDNA levels in subjects with a longer illness duration, worse functional status, and higher depressive symptoms. Our findings indicate that mitochondrial allostatic load contributes to BD, suggesting mitochondria represent a potential biological intersection point that could contribute to impaired cellular resilience and increased vulnerability to stress and mood episodes. Ultimately, by linking mitochondrial dysfunction to disease progression and poor outcomes, we might be able to build a predictive marker that explains how mitochondrial function and its regulation contribute to BD development and that may eventually serve as a treatment guide for both old and new therapeutic targets.

Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.

Altered neurochemistry in the anterior white matter of bipolar children and adolescents: a multivoxel 1H MRS study.

Abnormalities within frontal lobe gray and white matter of bipolar disorder (BD) patients have been consistently reported in adult and pediatric studies, yet little is known about the neurochemistry of the anterior white matter (AWM) in pediatric BD and how medication status may affect it. The present cross-sectional 3T 1H MRS study is the first to use a multivoxel approach to study the AWM of BD youth. Absolute metabolite levels from four bilateral AWM voxels were collected from 49 subjects between the ages of 8 and 18 (25 healthy controls (HC); 24 BD) and quantified. Our study found BD subjects to have lower levels of N-acetylaspartate (NAA) and glycerophosphocholine plus phosphocholine (GPC + PC), metabolites that are markers of neuronal viability and phospholipid metabolism and have also been implicated in adult BD. Further analysis indicated that the observed patterns were mostly driven by BD subjects who were medicated at the time of scanning and had an ADHD diagnosis. Although limited by possible confounding effects of mood state, medication, and other mood comorbidities, these findings serve as evidence of altered neurochemistry in BD youth that is sensitive to medication status and ADHD comorbidity.

Brain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders : Evidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group.

Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = -0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.

Investigation of endophenotype potential of decreased fractional anisotropy in pediatric bipolar disorder patients and unrelated offspring of bipolar disorder patients.

BACKGROUND: Bipolar disorder (BD) is a severe psychiatric disorder associated with structural and functional brain abnormalities, some of which have been found in unaffected relatives as well. In this study, we examined the potential role of decreased fractional anisotropy (FA) as a BD endophenotype, in adolescents at high risk for BD. METHODS: We included 15 offspring of patients with BD, 16 pediatric BD patients, and 16 matched controls. Diffusion weighted scans were obtained on a 3T scanner using an echo-planar sequence. Scans were segmented using FreeSurfer. RESULTS: Our results showed significantly decreased FA in six brain areas of offspring group; left superior temporal gyrus (LSTG; P < .0001), left transverse temporal gyrus (LTTG; P = .002), left banks of the superior temporal sulcus (LBSTS; P = .002), left anterior cingulum (LAC; P = .003), right temporal pole (RTP; P = .004) and left frontal pole (LFP; P = .017). On analysis, LSTG, LAC, and RTP demonstrated a potential to be an endophenotype when comparing all three groups. FA values in three regions, LBSTS, LTTG, and LFP were increased only in controls. CONCLUSION: Our findings point at decreased FA as a possible endophenotype for BD, as they were found in children of patients with BD. Most of these areas were previously found to have morphological and functional changes in adult and pediatric BD, and are thought to play important roles in affected domains of functioning. Prospective follow up studies should be performed to detect reliability of decreased FA as an endophenotype and effects of treatment on FA.

The use of component-wise gradient boosting to assess the possible role of cognitive measures as markers of vulnerability to pediatric bipolar disorder.

BACKGROUND AND AIMS: Cognitive impairments are primary hallmarks symptoms of bipolar disorder (BD). Whether these deficits are markers of vulnerability or symptoms of the disease is still unclear. This study used a component-wise gradient (CGB) machine learning algorithm to identify cognitive measures that could accurately differentiate pediatric BD, unaffected offspring of BD parents, and healthy controls. METHODS: 59 healthy controls (HC; 11.19 ± 3.15 yo; 30 girls), 119 children and adolescents with BD (13.31 ± 3.02 yo, 52 girls) and 49 unaffected offspring of BD parents (UO; 9.36 ± 3.18 yo; 22 girls) completed the CANTAB cognitive battery. RESULTS: CGB achieved accuracy of 73.2% and an AUROC of 0.785 in classifying individuals as either BD or non-BD on a dataset held out for validation for testing. The strongest cognitive predictors of BD were measures of processing speed and affective processing. Measures of cognition did not differentiate between UO and HC. CONCLUSIONS: Alterations in processing speed and affective processing are markers of BD in pediatric populations. Longitudinal studies should determine whether UO with a cognitive profile similar to that of HC are at less or equal risk for mood disorders. Future studies should include relevant measures for BD such as verbal memory and genetic risk scores.

Elevated Plasma S100B, Psychotic Symptoms, and Cognition in Schizophrenia.

S100B is a calcium binding protein mainly produced by glial cells. Previous studies have shown elevated levels of S100B in patients with schizophrenia. We measured S100B levels in fasting plasma of 39 patients with schizophrenia and 19 adult healthy controls. We used linear regression to compare S100B between patients and controls. In patients only, we also investigated the relationship between S100B levels and psychotic symptoms (assessed by the Positive and Negative Syndrome Scale), and cognitive function (assessed by the NIH Toolbox Cognition Battery), respectively by calculating Pearson's correlation coefficients. Mean plasma S100B was significantly higher in the patient group than in the control group. There were no significant correlations between plasma S100B and psychotic symptoms or cognition.

Identification and individualized prediction of clinical phenotypes in bipolar disorders using neurocognitive data, neuroimaging scans and machine learning.

Diagnosis, clinical management and research of psychiatric disorders remain subjective - largely guided by historically developed categories which may not effectively capture underlying pathophysiological mechanisms of dysfunction. Here, we report a novel approach of identifying and validating distinct and biologically meaningful clinical phenotypes of bipolar disorders using both unsupervised and supervised machine learning techniques. First, neurocognitive data were analyzed using an unsupervised machine learning approach and two distinct clinical phenotypes identified namely; phenotype I and phenotype II. Second, diffusion weighted imaging scans were pre-processed using the tract-based spatial statistics (TBSS) method and 'skeletonized' white matter fractional anisotropy (FA) and mean diffusivity (MD) maps extracted. The 'skeletonized' white matter FA and MD maps were entered into the Elastic Net machine learning algorithm to distinguish individual subjects' phenotypic labels (e.g. phenotype I vs. phenotype II). This calculation was performed to ascertain whether the identified clinical phenotypes were biologically distinct. Original neurocognitive measurements distinguished individual subjects' phenotypic labels with 94% accuracy (sensitivity=92%, specificity=97%). TBSS derived FA and MD measurements predicted individual subjects' phenotypic labels with 76% and 65% accuracy respectively. In addition, individual subjects belonging to phenotypes I and II were distinguished from healthy controls with 57% and 92% accuracy respectively. Neurocognitive task variables identified as most relevant in distinguishing phenotypic labels included; Affective Go/No-Go (AGN), Cambridge Gambling Task (CGT) coupled with inferior fronto-occipital fasciculus and callosal white matter pathways. These results suggest that there may exist two biologically distinct clinical phenotypes in bipolar disorders which can be identified from healthy controls with high accuracy and at an individual subject level. We suggest a strong clinical utility of the proposed approach in defining and validating biologically meaningful and less heterogeneous clinical sub-phenotypes of major psychiatric disorders.

Are self-rated and behavioural measures of impulsivity in bipolar disorder mainly related to comorbid substance use problems?

INTRODUCTION: Impulsivity is a multidimensional feature observed in bipolar disorder (BD) and substance use disorder (SUD). We previously found a relationship between SUD and risk taking in BD. It is still unclear whether self-rated and behavioral impulsivity measures differ between BD with and without comorbid SUD, or are specific to BD. METHODS: 93 adults with BD with comorbid SUD, 91 BD without SUD, and 93 healthy controls (HC) were administered the Barratt Impulsivity Scale (BIS), the Behavioral Inhibition/Behavioral Activation System Scale (BIS/BAS), and the Cambridge Neuropsychological Test Automated Battery. Analyses compared impulsivity measures across groups controlling for age. Discriminant function analyses (DFA) assessed the combination of variables effectively predicting group membership. RESULTS: BD displayed increased BIS, BIS/BAS scores, reduced performance on the Cambridge Gambling and Rapid Visual Processing, and Affective Go/No-Go tasks compared to HC. Comparisons between BD with and without SUD showed increased BIS Motor impulsiveness. The overall predictive power of DFA was weak. CONCLUSIONS: Some facets of impulsivity are a core trait of BD and are partially independent from the presence of SUD. Motor impulsiveness may be distinctive of BD+SUD. More research is needed to understand the role of impulsive behaviors as risk factors for relapse in SUD.

Interaction of BDNF with cytokines in chronic schizophrenia.

Brain-derived neurotrophic factor (BDNF) interacts with cytokines. Although both BDNF and cytokines occur at abnormal levels in schizophrenia patients, their interactions have not yet been examined. We therefore compared serum BDNF, TNF-α, interleukin (IL)-2, IL-6, and IL-8 levels in 92 chronically medicated schizophrenia patients and 60 healthy controls. We correlated these serum levels within these subject groups with each other and with clinical symptoms assessed according to the Positive and Negative Syndrome Scale (PANSS). Compared to the control group, the schizophrenia patients had significantly lower BDNF and TNF-α levels, and higher IL-2, IL-6, and IL-8 levels. The patients also showed a significant positive correlation between BDNF and both IL-2 and IL-8 levels, and low BDNF and TNF-α levels together were associated with poor performance on the PANSS cognitive factor. Thus, an interaction between cytokines and neurotrophic factors may be implicated in the pathophysiology of chronic schizophrenia. In particular, the cytokine TNF-α may interact with BNDF causing cognitive impairment.

Development and validation of a brain maturation index using longitudinal neuroanatomical scans.

BACKGROUND: Major psychiatric disorders are increasingly being conceptualized as 'neurodevelopmental', because they are associated with aberrant brain maturation. Several studies have hypothesized that a brain maturation index integrating patterns of neuroanatomical measurements may reliably identify individual subjects deviating from a normative neurodevelopmental trajectory. However, while recent studies have shown great promise in developing accurate brain maturation indices using neuroimaging data and multivariate machine learning techniques, this approach has not been validated using a large sample of longitudinal data from children and adolescents. METHODS: T1-weighted scans from 303 healthy subjects aged 4.88 to 18.35years were acquired from the National Institute of Health (NIH) pediatric repository (http://www.pediatricmri.nih.gov). Out of the 303 subjects, 115 subjects were re-scanned after 2years. The least absolute shrinkage and selection operator algorithm (LASSO) was 'trained' to integrate neuroanatomical changes across chronological age and predict each individual's brain maturity. The resulting brain maturation index was developed using first-visit scans only, and was validated using second-visit scans. RESULTS: We report a high correlation between the first-visit chronological age and brain maturation index (r=0.82, mean absolute error or MAE=1.69years), and a high correlation between the second-visit chronological age and brain maturation index (r=0.83, MAE=1.71years). The brain maturation index captured neuroanatomical volume changes between the first and second visits with an MAE of 0.27years. CONCLUSIONS: The brain maturation index developed in this study accurately predicted individual subjects' brain maturation longitudinally. Due to its strong clinical potentials in identifying individuals with an abnormal brain maturation trajectory, the brain maturation index may allow timely clinical interventions for individuals at risk for psychiatric disorders.

The management of cognitive impairment in bipolar disorder: current status and perspectives.

Bipolar disorder (BD) is associated with important cognitive deficits that persist during the periods of remission. Although these deficits seem to play an important role in the functional impairment experienced by bipolar patients, evidence regarding their clinical management is scant. We revised the databases PubMed, MEDLINE, and clinicaltrials.gov, searching for studies focusing on the pharmacological and nonpharmacological treatment of cognitive deficits among bipolar patients. In addition, a manual search of bibliographical cross-references was performed. Currently, there is no Food and Drug Administration-approved pharmacological agent for the management of cognitive deficits in BD. A number of agents have been tested in the treatment of cognitive deficits in BD, with mixed results. Nonpharmacological interventions, such as cognitive remediation and noninvasive brain stimulation techniques, seem promising, but their role has not yet been properly explored among bipolar patients. Additional studies, aiming at evaluating the efficacy of interventions combining cognitive rehabilitation and biological treatments, are highly desirable.

Prediction of pediatric bipolar disorder using neuroanatomical signatures of the amygdala.

OBJECTIVES: Pediatric bipolar disorder is currently diagnosed based on signs and symptoms, and without objective diagnostic biomarkers. In the present study, we investigated the utility of structural neuroanatomical signatures of the amygdala to objectively differentiate individual subjects with pediatric bipolar disorder from matched healthy controls. METHODS: Structural T1 -weighted neuroimaging scans were obtained from 16 children and adolescents with unmedicated DSM-IV bipolar disorder (11 males, five females) and 16 matched healthy controls (11 males, five females). Voxel-based gray matter morphometric features extracted from a bilateral region-of-interest within the amygdala were used to develop a multivariate pattern analysis model which was utilized in predicting novel or 'unseen' individual subjects as either bipolar disorder or healthy controls. RESULTS: The model assigned 25 out of 32 subjects the correct label (bipolar disorder/healthy) translating to a 78.12% diagnostic accuracy, 81.25% sensitivity, 75.00% specificity, 76.47% positive predictive value, and 80.00% negative predictive value and an area under the receiver operating characteristic curve (ROC) of 0.81. The predictions were significant at p = 0.0014 (χ(2) test p-value). CONCLUSIONS: These results reaffirm previous reports on the existence of neuroanatomical abnormalities in the amygdala of pediatric patients with bipolar disorder. Remarkably, the present study also demonstrates that neuroanatomical signatures of the amygdala can predict individual subjects with bipolar disorder with a relatively high specificity and sensitivity. To the best of our knowledge, this is the first study to present a proof-of-concept diagnostic marker of pediatric bipolar disorder based on structural neuroimaging scans of largely medication-naïve patients.

Impulsivity in children and adolescents with mood disorders and unaffected offspring of bipolar parents.

OBJECTIVE: Increased impulsivity seems to be present across all phases of bipolar disorder (BD). Impulsivity may therefore represent an endophenotype for BD, if it is also found among normal individuals at high genetic risk for mood disorders. In this study, we assessed impulsivity across four different groups of children and adolescents: patients with BD, major depressive disorder (MDD) patients, unaffected offspring of bipolar parents (UO), and healthy controls (HC). SUBJECTS AND METHODS: 52 patients with BD, 31 with MDD, 20 UO, and 45 HC completed the Barratt Impulsiveness Scale (BIS-11), an instrument designed to measure trait impulsivity. RESULTS: UO displayed significantly higher total BIS-11 impulsivity scores than HC (p=0.02) but lower scores than BD patients (F=27.12, p<0.01). Multiple comparison analysis revealed higher BIS-11 total scores among BD patients when compared to HC (p<0.01) and UO (p<0.01). MDD patients had higher BIS-11 scores when compared to HC (p<0.01). Differences between MDD patients and UO, as well as between MDD and BD patients, were not statistically significant. CONCLUSION: Our findings suggest that trait impulsivity is increased among children and adolescents with mood disorders, as well as in unaffected individuals at high genetic risk for BD.

Is impulsivity a common trait in bipolar and unipolar disorders?

OBJECTIVES: Impulsivity is increased in bipolar and unipolar disorders during episodes and is associated with substance abuse disorders and suicide risk. Impulsivity between episodes predisposes to relapses and poor therapeutic compliance. However, there is little information about impulsivity during euthymia in mood disorders. We sought to investigate trait impulsivity in euthymic bipolar and unipolar disorder patients, comparing them to healthy individuals and unaffected relatives of bipolar disorder patients. METHODS: Impulsivity was evaluated by the Barratt Impulsiveness Scale (BIS-11A) in 54 bipolar disorder patients, 25 unipolar disorder patients, 136 healthy volunteers, and 14 unaffected relatives. The BIS-11A mean scores for all four groups were compared through the Games-Howell test for all possible pairwise combinations. Additionally, we compared impulsivity in bipolar and unipolar disorder patients with and without a history of suicide attempt and substance abuse disorder. RESULTS: Bipolar and unipolar disorder patients scored significantly higher than the healthy controls and unaffected relatives on all measures of the BIS-11A except for attentional impulsivity. On the attentional impulsivity measures there were no differences among the unaffected relatives and the bipolar and unipolar disorder groups, but all three of these groups scored higher than the healthy participant group. There was no difference in impulsivity between bipolar and unipolar disorder subjects with and without suicide attempt. However, impulsivity was higher among bipolar and unipolar disorder subjects with past substance use disorder compared to patients without such a history. CONCLUSIONS: Questionnaire-measured impulsivity appears to be relatively independent of mood state in bipolar and unipolar disorder patients; it remains elevated in euthymia and is higher in individuals with past substance abuse. Elevated attentional and lower non-planning impulsivity in unaffected relatives of bipolar disorder patients distinguished them from healthy participants, suggesting that increased attentional impulsivity may predispose to development of affective disorders, while reduced attentional impulsivity may be protective.

Temperament and character traits in children and adolescents with major depressive disorder: a case-control study.

OBJECTIVES: To evaluate temperament and character traits using the Junior Temperament and Character Inventory (JTCI) in children and adolescents with major depressive disorder (MDD) in comparison with healthy control subjects (HC), and to verify if comorbidity with disruptive behavioral disorders and being currently depressed influence JTCI scores. METHODS: A case-control study comprising 41 MDD children/adolescents matched to 40 HC by gender and age (8-17years). All participants were assessed diagnostically with the Kiddie Schedule for Affective Disorders and Schizophrenia - Present and Lifetime (K-SADS-PL). Temperament and character traits were measured with the parent and child versions of JTCI, and depression was evaluated with the Children's Depression Rating Scale (CDRS). RESULTS: According to child and parent data, MDD subjects had significantly higher scores on harm avoidance and novelty seeking, and lower scores on reward dependence, persistence, self-directedness and cooperativeness compared with HC. According to parent data only, MDD subjects significantly differed from HC on self-transcendence (lower spirituality scores and higher fantasy scores). Comorbidity with disruptive behavioral disorders exerted influence on almost all dimensions, in general increasing the mean differences between MDD and HC subjects. Also, being currently depressed did not influence the results, except for reward dependence according to parent data. LIMITATIONS: The cross-sectional nature of the study and its limited sample size. CONCLUSIONS: MDD children/adolescents have a different temperament and character profile compared to HC subjects. This study supports previous findings of trait-like characteristics of harm avoidance and self-directedness.

Trait impulsivity is increased in bipolar disorder patients with comorbid alcohol use disorders.

BACKGROUND: Up to 60% of bipolar disorder (BD) patients develop alcohol use disorders (AUD) at some point in their lives. The causes of this highly prevalent comorbidity are unknown. High trait impulsivity characterizes both isolated BD and AUD and may be a link to explain the association between BD and AUD. In this study, our aims were to investigate whether BD patients with comorbid AUD would present higher trait impulsivity levels compared to BD patients without comorbid AUD, and whether trait impulsivity levels differ within subgroups of BD according to the subcategory of AUD (abuse vs. dependence, alcoholism alone vs. alcoholism plus drug use disorders). SAMPLING AND METHODS: Forty-seven outpatients with BD with comorbid AUD (alcoholic BD group) were compared to 66 outpatients with BD alone (nonalcoholic BD group) and to 90 healthy controls (HC). BD and AUD diagnoses were obtained using the Structured Clinical Interview for DSM-IV diagnoses. Impulsivity was assessed using the Barratt Impulsiveness Scale (BIS-11), a self-report instrument that measures trait impulsivity in three domains: nonplanning, attentional and motor. RESULTS: Alcoholic BD patients scored significantly higher than nonalcoholic BD and HC on the total and on each subscale BIS scores. Within the alcoholic BD patients, alcohol abusers and alcohol dependents did not statistically differ from each other on the BIS-11 scores. BD patients with AUD plus drug use disorders presented statistically higher nonplanning impulsivity than BD patients with AUD alone. CONCLUSIONS: This was a cross-sectional study and causal inferences about the relationship between impulsivity and the comorbidity phenomenon cannot be made. Increased impulsivity may be a trait marker for the co-occurrence between BD and AUD, and mediate some severe manifestations of this comorbidity.

Overdiagnosis of bipolar disorder: a critical analysis of the literature.

Bipolar disorder (BD) is considered one of the most disabling mental conditions, with high rates of morbidity, disability, and premature death from suicide. Although BD is often misdiagnosed as major depressive disorder, some attention has recently been drawn to the possibility that BD could be overdiagnosed in some settings. The present paper focuses on a critical analysis of the overdiagnosis issue among bipolar patients. It includes a review of the available literature findings, followed by some recommendations aiming at optimizing the diagnosis of BD and increasing its reliability.

Mitochondrial Health Index Correlates with Plasma Circulating Cell-Free Mitochondrial DNA in Bipolar Disorder.

Background: Although mitochondria dysfunction is known to play an essential role in the pathophysiology of bipolar disorder (BD), there is a glaring gap in our understanding of how mitochondrial dysfunction can modulate clinical phenotypes. This study aimed to evaluate the composite mitochondrial health index (MHI) in BD subjects and non-psychiatry controls (Non-psychiatry controls). We will also explore whether lower MIH will be related to higher cell-free mtDNA (ccf-mtDNA) levels and poor clinical outcomes. Methods: Fourteen BD-I patients and 16 age- and sex-matched non-psychiatry controls were enrolled for this study. Peripheral blood mononuclear cells (PBMCs) were used to measure the enzymatic activities of citrate synthase and complexes I, II, and IV and mtDNA copy number. ccf-mtDNA was evaluated by qPCR in plasma. Mitochondrial quality control (MQC) proteins were evaluated by western blotting. Results: One-Way ANCOVA after controlling for age, sex, body mass index (BMI), and smoking status showed that patients with BD present a decrease in the MHI compared to non-psychiatry controls, and higher ccf-mtDNA levels, which was negatively correlated with MHI. Because the MQC network is essential to maintain mitochondrial health, we also evaluated the relationship between MQC-related proteins with MHI and ccf-mtDNA. Our results showed that MHI negatively correlated with Fis-1 and positively with Opa-1 and LC3. Moreover, we found a negative correlation between ccf-mtDNA, Opa-1, and LC3 and a positive correlation between cff-mtDNA and Fis-1. Finally, we found that subjects with longer illness duration, higher depressive symptom scores, and worse functional status had lower MHI and higher ccf-mtDNA. Conclusion: In summary, the present findings corroborate previous studies and provide strong support for the hypothesis that mitochondrial regulation and function are integral parts of the pathogenesis of BD.