Editorial: A Roadmap for Advancing the Field in Early-Onset Psychosis.

The number of umbrella reviews, the systematic reviews of all systematic reviews and meta-analyses in a specified subject, have increased exponentially in recent years. In February 2024, a PubMed search with the term "umbrella review" yielded 840 publications in 2023, compared with 77 in 2013, and 16 in 2003. As the number of scientific publications grows, also does the need to synthesize the current state of knowledge to guide research efforts, clinical practice, and health policies.1,2.

Brain functional activation and first mood episode in youth at risk for bipolar disorder.

BACKGROUND: In order to identify biomarkers of prodromal mood disorders, we examined functional brain activation in children and adolescent at familial risk for bipolar disorder. METHODS: Offspring of parents with bipolar I disorder (at-risk youth; N = 115, mean ± SD age: 13.6 ± 2.7; 54 % girls) and group-matched offspring of healthy parents (healthy controls; N = 58, mean ± SD age: 14.2 ± 3.0; 53 % girls) underwent functional magnetic resonance imaging while performing a continuous performance task with emotional and neutral distracters. At baseline, at-risk youth had no history of mood episodes or psychotic disorders. Subjects were followed longitudinally until developing their first mood episode or being lost to follow-up. Standard event-related region-of-interest (ROI) analyses were performed to compare brain activation at baseline between groups and in survival analyses. RESULTS: At baseline, at-risk youth exhibited reduced activation to emotional distracters in the right ventrolateral prefrontal cortex (VLPFC) (p = 0.04). Activation was not significantly altered in additional ROIs, including left VLPFC, bilateral amygdala, caudate, or putamen. In those at-risk youth who developed their first mood episode during follow-up (n = 17), baseline increased activation in right VLPFC, right caudate, and right putamen activation predicted the development of a mood episode. LIMITATIONS: Sample size of converters, loss to follow-up, and number of statistical comparisons. CONCLUSIONS: We found preliminary evidence that a reduced activation in right VLPFC might be a marker of risk for or resilience to mood disorders in at-risk youth. Conversely, an increased activation in the right VLPFC, caudate, and putamen might indicate an increased risk for the later development of their first mood episode.

Changes in the structural brain connectome over the course of a nonrandomized clinical trial for acute mania.

Disrupted topological organization of brain functional networks has been widely reported in bipolar disorder. However, the potential clinical implications of structural connectome abnormalities have not been systematically investigated. The present study included 109 unmedicated subjects with acute mania who were assigned to 8 weeks of treatment with quetiapine or lithium and 60 healthy controls. High resolution 3D-T1 weighted magnetic resonance images (MRI) were collected from both groups at baseline, week 1 and week 8. Brain networks were constructed based on the similarity of morphological features across brain regions and analyzed using graph theory approaches. At baseline, individuals with bipolar disorder illness showed significantly lower clustering coefficient (Cp) (p = 0.012) and normalized characteristic path length (λ) (p = 0.004) compared to healthy individuals, as well as differences in nodal centralities across multiple brain regions. No baseline or post-treatment differences were identified between drug treatment conditions, so change after treatment were considered in the combined treatment groups. Relative to healthy individuals, differences in Cp, λ and cingulate gyrus nodal centrality were significantly reduced with treatment; changes in these parameters correlated with changes in Young Mania Rating Scale scores. Baseline structural connectome matrices significantly differentiated responder and non-responder groups at 8 weeks with 74% accuracy. Global and nodal network alterations evident at baseline were normalized with treatment and these changes associated with symptomatic improvement. Further, baseline structural connectome matrices predicted treatment response. These findings suggest that structural connectome abnormalities are clinically significant and may be useful for predicting clinical outcome of treatment and tracking drug effects on brain anatomy in bipolar disorder. CLINICAL TRIALS REGISTRATION: Name: Functional and Neurochemical Brain Changes in First-episode Bipolar Mania Following Successful Treatment with Lithium or Quetiapine. URL: https://clinicaltrials.gov/ . REGISTRATION NUMBER: NCT00609193. Name: Neurofunctional and Neurochemical Markers of Treatment Response in Bipolar Disorder. URL: https://clinicaltrials.gov/ . REGISTRATION NUMBER: NCT00608075.

Structural connectivity associated with familial risk for mental illness: A meta-analysis of diffusion tensor imaging studies in relatives of patients with severe mental disorders.

Schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) are heritable conditions with overlapping genetic liability. Transdiagnostic and disorder-specific brain changes associated with familial risk for developing these disorders remain poorly understood. We carried out a meta-analysis of diffusion tensor imaging (DTI) studies to investigate white matter microstructure abnormalities in relatives that might correspond to shared and discrete biomarkers of familial risk for psychotic or mood disorders. A systematic search of PubMed and Embase was performed to identify DTI studies in relatives of SCZ, BD, and MDD patients. Seed-based d Mapping software was used to investigate global differences in fractional anisotropy (FA) between overall and disorder-specific relatives and healthy controls (HC). Our search identified 25 studies that met full inclusion criteria. A total of 1,144 relatives and 1,238 HC were included in the meta-analysis. The overall relatives exhibited decreased FA in the genu and splenium of corpus callosum (CC) compared with HC. This finding was found highly replicable in jack-knife analysis and subgroup analyses. In disorder-specific analysis, compared to HC, relatives of SCZ patients exhibited the same changes while those of BD showed reduced FA in the left inferior longitudinal fasciculus (ILF). The present study showed decreased FA in the genu and splenium of CC in relatives of SCZ, BD, and MDD patients, which might represent a shared familial vulnerability marker of severe mental illness. The white matter abnormalities in the left ILF might represent a specific familial risk for bipolar disorder.

N-acetylcysteine for depression and glutamate changes in the left prefrontal cortex in adolescents and young adults at risk for bipolar disorder: A pilot study.

AIMS: To investigate the mechanism of action of N-acetylcysteine (NAC) in depressive symptoms in young individuals at familial risk for bipolar disorder. METHODS: We conducted an 8-week open label clinical trial of NAC 2400 mg/days in 15-24 years old depressed offspring of a bipolar I disorder parent, with baseline and endpoint proton magnetic resonance spectroscopy acquired within the left ventrolateral prefrontal cortex (VLPFC). RESULTS: Nine participants were enrolled and finished the study. NAC significantly improved depressive and anxiety symptom scores, and clinical global impression (all p < .001). There was a non-significant reduction in glutamate levels in the left VLPFC. Reduction in depressive symptom scores was positively associated with reduction in glutamate levels in the left VLPFC (p = .007). CONCLUSIONS: This pilot study suggests that NAC might be efficacious for depressive symptoms in at-risk youth, and that its mechanism of action involves the modulation of glutamate in the left VLPFC.

Changes in the brain structural connectome after a prospective randomized clinical trial of lithium and quetiapine treatment in youth with bipolar disorder.

The goals of the current study were to determine whether topological organization of brain structural networks is altered in youth with bipolar disorder, whether such alterations predict treatment outcomes, and whether they are normalized by treatment. Youth with bipolar disorder were randomized to double-blind treatment with quetiapine or lithium and assessed weekly. High-resolution MRI images were collected from children and adolescents with bipolar disorder who were experiencing a mixed or manic episode (n = 100) and healthy youth (n = 63). Brain networks were constructed based on the similarity of morphological features across regions and analyzed using graph theory approaches. We tested for pretreatment anatomical differences between bipolar and healthy youth and for changes in neuroanatomic network metrics following treatment in the youth with bipolar disorder. Youth with bipolar disorder showed significantly increased clustering coefficient (Cp) (p = 0.009) and characteristic path length (Lp) (p = 0.04) at baseline, and altered nodal centralities in insula, inferior frontal gyrus, and supplementary motor area. Cp, Lp, and nodal centrality of the insula exhibited normalization in patients following treatment. Changes in these neuroanatomic parameters were correlated with improvement in manic symptoms but did not differ between the two drug therapies. Baseline structural network matrices significantly differentiated medication responders and non-responders with 80% accuracy. These findings demonstrate that both global and nodal structural network features are altered in early course bipolar disorder, and that pretreatment alterations in neuroanatomic features predicted treatment outcome and were reduced by treatment. Similar connectome normalization with lithium and quetiapine suggests that the connectome changes are a downstream effect of both therapies that is related to their clinical efficacy.

Association between poor tolerability of antidepressant treatment and brain functional activation in youth at risk for bipolar disorder

Objective: To investigate whether poor antidepressant tolerability is associated with functional brain changes in children and adolescents of parents with bipolar I disorder (at-risk youth). Methods: Seventy-three at-risk youth (ages 9-20 years old) who participated in a prospective study and had an available baseline functional magnetic resonance imaging (fMRI) scan were included. Research records were reviewed for the incidence of adverse reactions related to antidepressant exposure during follow-up. The sample was divided among at-risk youth without antidepressant exposure (n=21), at-risk youth with antidepressant exposure and no adverse reaction (n=12), at-risk youth with antidepressant-related adverse reaction (n=21), and healthy controls (n=20). The fMRI task was a continuous performance test with emotional distracters. Region-of-interest mean activation in brain areas of the fronto-limbic emotional circuit was compared among groups. Results: Right amygdala activation in response to emotional distracters significantly differed among groups (F3,66 = 3.1, p = 0.03). At-risk youth with an antidepressant-related adverse reaction had the lowest amygdala activation, while at-risk youth without antidepressant exposure had the highest activation (p = 0.004). Conclusions: Decreased right amygdala activation in response to emotional distracters is associated with experiencing an antidepressant-related adverse reaction in at-risk youth. Further studies to determine whether amygdala activation is a useful biomarker for antidepressant-related adverse events are needed.

N-acetylcysteine as an adjunctive treatment for bipolar depression: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: Previous studies and meta-analyses suggested that N-acetylcysteine (NAC) was superior to placebo in improving depression in bipolar disorder. However, more recent data, including two larger trials, found that NAC was no more effective than placebo. We conducted a meta-analysis to appraise the possible efficacy of NAC in treating bipolar depression. METHODS: A systematic review and meta-analysis of double-blind, placebo-controlled trials of NAC as a treatment augmentation strategy for bipolar depression was carried out in PubMed (1966-2020). We utilized random-effect analysis to evaluate improvement in depressive symptoms from baseline to endpoint as the primary efficacy measure. RESULTS: Six trials including 248 patients were included. Treatment augmentation with NAC showed a moderate effect size favoring NAC over placebo (d = 0.45, 95% C.I.: 0.06-0.84). There was substantial heterogeneity (I2  = 49%). Meta-regression analyses did not identify any moderator that might explain variation in heterogeneity, including baseline depressive symptom scores, mean NAC dose, or duration of study. CONCLUSIONS: Results from six clinical trials suggest that treatment augmentation with NAC for bipolar depression appears to be superior to placebo, with a moderate effect size, but a large confidence interval. Larger clinical trials, investigating possible moderating factors, such as NAC dose, treatment duration, baseline depression severity, or chronicity of illness, are warranted.

Individual prediction of symptomatic converters in youth offspring of bipolar parents using proton magnetic resonance spectroscopy.

Children of individuals with bipolar disorder (bipolar offspring) are at increased risk for developing mood disorders, but strategies to predict mood episodes are unavailable. In this study, we used support vector machine (SVM) to characterize the potential of proton magnetic resonance spectroscopy (1H-MRS) in predicting the first mood episode in youth bipolar offspring. From a longitudinal neuroimaging study, 19 at-risk youth who developed their first mood episode (converters), and 19 without mood episodes during follow-up (non-converters) were selected and matched for age, sex and follow-up time. Baseline 1H-MRS data were obtained from anterior cingulate cortex (ACC) and bilateral ventrolateral prefrontal cortex (VLPFC). Glutamate (Glu), myo-inositol (mI), choline (Cho), N-acetyl aspartate (NAA), and phosphocreatine plus creatine (PCr + Cr) levels were calculated. SVM with a linear kernel was adopted to classify converters and non-converters based on their baseline metabolites. SVM allowed the significant classification of converters and non-converters across all regions for Cho (accuracy = 76.0%), but not for other metabolites. Considering all metabolites within each region, SVM allowed the significant classification of converters and non-converters for left VLPFC (accuracy = 76.5%), but not for right VLPFC or ACC. The combined mI, PCr + Cr, and Cho from left VLPFC achieved the highest accuracy differentiating converters from non-converters (79.0%). Our findings from this exploratory study suggested that 1H-MRS levels of mI, Cho, and PCr + Cr from left VLPFC might be useful to predict the development of first mood episode in youth bipolar offspring using machine learning. Future studies that prospectively examine and validate these metabolites as predictors of mood episodes in high-risk individuals are necessary.

Medication exposure and predictors of first mood episode in offspring of parents with bipolar disorder: a prospective study

Objectives: To prospectively investigate whether baseline clinical characteristics and medication exposure predict development of major depressive disorder or bipolar disorder in offspring of parents with bipolar disorder. Methods: Youth aged 9-20 years with at least one biological parent with bipolar disorder and no prior history of mood or psychotic episodes (n=93) were prospectively evaluated and treated naturalistically during the study. Participants were divided into two groups: converters, defined as those who met DSM-IV criteria for a mood episode during follow-up (n=19); or non-converters (n=74). Logistic regression models were used to investigate associations between baseline clinical variables and medication exposure during follow-up and risk of developing a first mood episode (conversion). Results: Multivariate regression analyses showed that baseline anxiety disorders and subsyndromal mood disorders were associated with increased risk of conversion during follow-up. Adding medication exposure to the multivariate model showed that exposure to antidepressants during follow-up was associated with increased risk of conversion. Conclusions: Caution should be used when treating bipolar offspring with anxiety and/or emerging depressive symptoms using antidepressant agents, given the increased risk of developing a major mood disorder.

Association between poor tolerability of antidepressant treatment and brain functional activation in youth at risk for bipolar disorder.

OBJECTIVE: To investigate whether poor antidepressant tolerability is associated with functional brain changes in children and adolescents of parents with bipolar I disorder (at-risk youth). METHODS: Seventy-three at-risk youth (ages 9-20 years old) who participated in a prospective study and had an available baseline functional magnetic resonance imaging (fMRI) scan were included. Research records were reviewed for the incidence of adverse reactions related to antidepressant exposure during follow-up. The sample was divided among at-risk youth without antidepressant exposure (n=21), at-risk youth with antidepressant exposure and no adverse reaction (n=12), at-risk youth with antidepressant-related adverse reaction (n=21), and healthy controls (n=20). The fMRI task was a continuous performance test with emotional distracters. Region-of-interest mean activation in brain areas of the fronto-limbic emotional circuit was compared among groups. RESULTS: Right amygdala activation in response to emotional distracters significantly differed among groups (F3,66 = 3.1, p = 0.03). At-risk youth with an antidepressant-related adverse reaction had the lowest amygdala activation, while at-risk youth without antidepressant exposure had the highest activation (p = 0.004). CONCLUSIONS: Decreased right amygdala activation in response to emotional distracters is associated with experiencing an antidepressant-related adverse reaction in at-risk youth. Further studies to determine whether amygdala activation is a useful biomarker for antidepressant-related adverse events are needed.

Medication exposure and predictors of first mood episode in offspring of parents with bipolar disorder: a prospective study.

OBJECTIVES: To prospectively investigate whether baseline clinical characteristics and medication exposure predict development of major depressive disorder or bipolar disorder in offspring of parents with bipolar disorder. METHODS: Youth aged 9-20 years with at least one biological parent with bipolar disorder and no prior history of mood or psychotic episodes (n=93) were prospectively evaluated and treated naturalistically during the study. Participants were divided into two groups: converters, defined as those who met DSM-IV criteria for a mood episode during follow-up (n=19); or non-converters (n=74). Logistic regression models were used to investigate associations between baseline clinical variables and medication exposure during follow-up and risk of developing a first mood episode (conversion). RESULTS: Multivariate regression analyses showed that baseline anxiety disorders and subsyndromal mood disorders were associated with increased risk of conversion during follow-up. Adding medication exposure to the multivariate model showed that exposure to antidepressants during follow-up was associated with increased risk of conversion. CONCLUSIONS: Caution should be used when treating bipolar offspring with anxiety and/or emerging depressive symptoms using antidepressant agents, given the increased risk of developing a major mood disorder.

Brain structural correlates of familial risk for mental illness: a meta-analysis of voxel-based morphometry studies in relatives of patients with psychotic or mood disorders.

Schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) are heritable psychiatric disorders with partially overlapping genetic liability. Shared and disorder-specific neurobiological abnormalities associated with familial risk for developing mental illnesses are largely unknown. We performed a meta-analysis of structural brain imaging studies in relatives of patients with SCZ, BD, and MDD to identify overlapping and discrete brain structural correlates of familial risk for mental disorders. Search for voxel-based morphometry studies in relatives of patients with SCZ, BD, and MDD in PubMed and Embase identified 33 studies with 2292 relatives and 2052 healthy controls (HC). Seed-based d Mapping software was used to investigate global differences in gray matter volumes between relatives as a group versus HC, and between those of each psychiatric disorder and HC. As a group, relatives exhibited gray matter abnormalities in left supramarginal gyrus, right striatum, right inferior frontal gyrus, left thalamus, bilateral insula, right cerebellum, and right superior frontal gyrus, compared with HC. Decreased right cerebellar gray matter was the only abnormality common to relatives of all three conditions. Subgroup analyses showed disorder-specific gray matter abnormalities in left thalamus and bilateral insula associated with risk for SCZ, in left supramarginal gyrus and right frontal regions with risk for BD, and in right striatum with risk for MDD. While decreased gray matter in right cerebellum might be a common brain structural abnormality associated with shared risk for SCZ, BD, and MDD, regional gray matter abnormalities in neocortex, thalamus, and striatum appear to be disorder-specific.

Longitudinal proton spectroscopy study of the prefrontal cortex in youth at risk for bipolar disorder before and after their first mood episode.

OBJECTIVES: To investigate neurochemical abnormalities in the left and right ventrolateral prefrontal cortex (VLPFC) and anterior cingulate cortex (ACC) of youth at risk for bipolar disorder using proton magnetic resonance spectroscopy before and after their first mood episode. METHODS: Children and adolescents offspring of parents with bipolar I disorder (at-risk group, n = 117) and matched healthy controls (HC group, n = 61) were recruited at the University of Cincinnati. At-risk subjects had no lifetime major mood and psychotic disorders at baseline, and were followed up every 4 months to monitor for development of a major depressive, manic, hypomanic, or mixed mood episode. Levels of N-acetyl-aspartate (NAA), phosphocreatine plus creatine (PCr + Cr), choline-containing compounds, myo-inositol, and glutamate were determined using LCModel and corrected for partial volume effects. RESULTS: There were no baseline differences in metabolite levels for any of the brain regions between at-risk and HC youth. Nineteen at-risk subjects developed a first mood episode during follow-up. Survival analyses showed that baseline PCr + Cr levels in the left VLPFC significantly predicted a mood episode during follow-up in the at-risk group (HR: 0.47, 95% CI: 0.27-0.82, P = 0.008). There were no longitudinal changes in metabolites levels in the VLPFC and ACC before and after a mood episode in at-risk subjects. CONCLUSIONS: We found no evidence for abnormal proton spectroscopy metabolite levels in the VLPFC and ACC of at-risk youth, prior and after the development of their first mood episode. Preliminary findings of association between baseline PCr + Cr levels in the left VLPFC and risk to develop a mood episode warrant further investigation.

The association between social skills deficits and family history of mood disorder in bipolar I disorder

Objective: To compare social skills and related executive functions among bipolar disorder (BD) patients with a family history of mood disorders (FHMD), BD patients with no FHMD and healthy control (HCs). Methods: We evaluated 20 euthymic patients with FHMD, 17 euthymic patients without FHMD, and 31 HCs using the Social Skills Inventory (SSI) and a neuropsychological battery evaluating executive function, inhibitory control, verbal fluency and estimated intelligence. Results: Both BD groups had lower SSI scores than controls. Scores for one subfactor of the social skills questionnaire, conversational skills and social performance, were significantly lower among patients with FHMD than among patients without FHMD (p = 0.019). Both groups of BD patients exhibited significant deficits in initiation/inhibition, but only BD patients with FHMD had deficits in verbal fluency, both compared to HC. There were no associations between social skills questionnaire scores and measures of cognitive function. Conclusion: Euthymic BD patients have lower social skills and executive function performance than HC. The presence of FHMD among BD patients is specifically associated with deficits in conversational and social performance skills, in addition to deficits in verbal fluency. Both characteristics might be associated with a common genetically determined pathophysiological substrate.

Lithium-associated anterior cingulate neurometabolic profile in euthymic Bipolar I disorder: A 1H-MRS study.

OBJECTIVE: In the treatment of Bipolar disorder (BD), achieving euthymia is highly complex and usually requires a combination of mood stabilizers. The mechanism of action in stabilizing mood has not been fully elucidated, but alterations in N-Acetylaspartate (NAA), Myo-Inositol (mI) and Choline (Cho) have been implicated. Proton magnetic resonance spectroscopy (1H-MRS) is the gold standard technique for measuring brain NAA, Cho and mI in vivo. The objective of this study was to investigate the association of lithium use in BD type I and brain levels of NAA, mI and Cho in the (anterior cingulate cortex) ACC. METHODS: 129 BD type I subjects and 79 healthy controls (HC) were submitted to a 3-Tesla brain magnetic resonance imaging scan (1H-MRS) using a PRESS ACC single voxel (8cm3) sequence. RESULTS: BD patients exhibited higher NAA and Cho levels compared to HC. Lithium prescription was associated with lower mI (combination + monotherapy) and higher NAA levels (monotherapy). CONCLUSION: The results observed add to the knowledge about the mechanisms of action of mood stabilizers on brain metabolites during euthymia. Additionally, the observed decrease in mI levels associated with lithium monotherapy is an in vivo finding that supports the inositol-depletion hypothesis of lithium pharmacodynamics.

Discrete patterns of cortical thickness in youth with bipolar disorder differentially predict treatment response to quetiapine but not lithium.

The need for treatment response predictive biomarkers is being increasingly recognized in children and adolescents with psychiatric disorders. Structural gray matter abnormalities as a predictor of treatment outcome in pediatric bipolar disorder have not been systematically investigated, especially early in the illness course. With a prospective longitudinal study design, the present study enrolled 52 bipolar adolescents with no history of treatment with mood stabilizers or a therapeutic dose of antipsychotic drugs and 31 healthy controls. Patients were randomly assigned to treatment with quetiapine or lithium after pretreatment data collection. A hierarchical cluster analysis was performed using pretreatment cortical thickness data that identified two discrete patient subgroups. Compared to healthy subjects, patients in subgroup 1 (n = 16) showed widespread greater cortical thickness mainly across heteromodal cortex but also involving some regions of unimodal cortex, while those in subgroup 2 (n = 36) showed regional cortical thinning mainly in superior temporal and superior parietal regions. Patients within subgroup 1 showed a significantly higher response rate to quetiapine than those in subgroup 2 (100% vs 53%). No statistically significant difference was found in lithium response rate between the patient subgroups (63% vs 53%). Pretreatment clinical ratings and neuropsychological data did not differ across subgroups. Our findings suggest the existence of distinct and clinically relevant subgroups of pediatric bipolar patients, as defined by pattern of cortical thickness. These groups appear to differentially respond to antipsychotic treatment-notably with greater cortical thickness relative to controls predicting better treatment response.

Changes in amygdala, cerebellum, and nucleus accumbens volumes in bipolar patients treated with lamotrigine.

The neural mechanisms underlying the therapeutic effects of lamotrigine in bipolar depression are still unexplored. This preliminary study compares the effects of a 12-week treatment with lamotrigine on brain volumes in adults with bipolar disorder (BD).12 BD type II patients (age: 49.33 ± 9.95 years, 3 males, 9 females) and 12 age and gender-matched healthy controls (HC) (HC; age: 41 ± 8.60 years, 3 males, 9 females). BD patients were initially administered 25 mg/day of lamotrigine, which was progressively escalated to 200 mg/d. BD participants underwent brain imaging prior to and following lamotrigine treatment. A 50% reduction in depressive scores indicated "remission". Bayesian general linear models controlled for age, gender and intracranial volume were used to examine changes in relevant brain region following treatment. A posterior probability > 0.90 indicated evidence that there was an effect of diagnosis or remission on brain volumes. Probability distributions of interaction effects between remission and time indicated that BD responders displayed decreased amygdala, cerebellum and nucleus accumbens volumes following lamotrigine treatment. No serious adverse side effects were reported. The antidepressant effects of lamotrigine may be linked to volumetric changes in brain regions involved in mood and emotional regulation. These findings are preliminary and replication in a larger sample is warranted.

Anterior Cingulate Cortex Glutamatergic Metabolites and Mood Stabilizers in Euthymic Bipolar I Disorder Patients: A Proton Magnetic Resonance Spectroscopy Study.

BACKGROUND: Bipolar disorder is a chronic and recurrent illness characterized by depressive and manic episodes. Proton magnetic resonance spectroscopy (1H-MRS) studies have demonstrated glutamate (Glu) system abnormalities in BD, but it is unclear how Glu varies among mood states and how medications modulate it. The objective of this study was to investigate the influence of mood stabilizers on anterior cingulate cortex Glu levels using 1H-MRS during euthymia. METHODS: One hundred twenty-eight bipolar I disorder (BDI) euthymic subjects and 80 healthy control subjects underwent 3T brain 1H-MRS imaging examination including acquisition of an anterior cingulate cortex single voxel (8 cm3) 1H-MRS, based on a point resolved spectroscopy (PRESS) sequence with an echo time of 80 ms and a repetition time of 1500 ms (BIPUSP MRS study). The Glu system was described by measuring Glu and the sum of Glu and glutamine (Glx) using creatine (Cre) as a reference. RESULTS: Euthymic BDI subjects presented with higher ratios of Glu/Cre and Glx/Cre compared to healthy control subjects. Glu/Cre ratios were lower among patients using anticonvulsants, while Glx/Cre did not differ between the two groups. Lithium, antipsychotics, and antidepressants did not influence Glu/Cre or Glx/Cre. CONCLUSIONS: We reported Glu/Cre and Glx abnormalities in the largest sample of euthymic BDI patients studied by 1H-MRS to date. Our data indicate that both Glu/Cre and Glx/Cre are elevated in BDI during euthymia regardless of medication effects, reinforcing the hypothesis of glutamatergic abnormalities in BD. Furthermore, we found an effect of anticonvulsants on Glu/Cre during euthymia, which might indicate a mechanism of mood stabilization in BD.

The association between social skills deficits and family history of mood disorder in bipolar I disorder.

OBJECTIVE: To compare social skills and related executive functions among bipolar disorder (BD) patients with a family history of mood disorders (FHMD), BD patients with no FHMD and healthy control (HCs). METHODS: We evaluated 20 euthymic patients with FHMD, 17 euthymic patients without FHMD, and 31 HCs using the Social Skills Inventory (SSI) and a neuropsychological battery evaluating executive function, inhibitory control, verbal fluency and estimated intelligence. RESULTS: Both BD groups had lower SSI scores than controls. Scores for one subfactor of the social skills questionnaire, conversational skills and social performance, were significantly lower among patients with FHMD than among patients without FHMD (p = 0.019). Both groups of BD patients exhibited significant deficits in initiation/inhibition, but only BD patients with FHMD had deficits in verbal fluency, both compared to HC. There were no associations between social skills questionnaire scores and measures of cognitive function. CONCLUSION: Euthymic BD patients have lower social skills and executive function performance than HC. The presence of FHMD among BD patients is specifically associated with deficits in conversational and social performance skills, in addition to deficits in verbal fluency. Both characteristics might be associated with a common genetically determined pathophysiological substrate.