Possible Role of Correlation Coefficients and Network Analysis of Multiple Intracellular Proteins in Blood Cells of Patients with Bipolar Disorder in Studying the Mechanism of Lithium Responsiveness: A Proof-Concept Study.

Background: The mechanism of lithium treatment responsiveness in bipolar disorder (BD) remains unclear. The aim of this study was to explore the utility of correlation coefficients and protein-to-protein interaction (PPI) network analyses of intracellular proteins in monocytes and CD4+ lymphocytes of patients with BD in studying the potential mechanism of lithium treatment responsiveness. Methods: Patients with bipolar I or II disorder who were diagnosed with the MINI for DSM-5 and at any phase of the illness with at least mild symptom severity and received lithium (serum level ≥ 0.6 mEq/L) for 16 weeks were divided into two groups, responders (≥50% improvement in Montgomery-Asberg Depression Rating Scale and/or Young Mania Rating Scale scores from baseline) and non-responders. Twenty-eight intracellular proteins/analytes in CD4+ lymphocytes and monocytes were analyzed with a tyramine-based signal-amplified flow cytometry procedure. Correlation coefficients between analytes at baseline were estimated in both responders and non-responders and before and after lithium treatment in responders. PPI network, subnetwork, and pathway analyses were generated based on fold change/difference in studied proteins/analytes between responders and non-responders. Results: Of the 28 analytes from 12 lithium-responders and 11 lithium-non-responders, there were more significant correlations between analytes in responders than in non-responders at baseline. Of the nine lithium responders with pre- and post-lithium blood samples available, the correlations between most analytes were weakened after lithium treatment with cell-type specific patterns in CD4+ lymphocytes and monocytes. PPI network/subnetwork and pathway analyses showed that lithium response was involved in four pathways, including prolactin, leptin, neurotrophin, and brain-derived neurotrophic factor pathways. Glycogen synthase kinase 3 beta and nuclear factor NF-kappa-B p65 subunit genes were found in all four pathways. Conclusions: Using correlation coefficients, PPI network/subnetwork, and pathway analysis with multiple intracellular proteins appears to be a workable concept for studying the mechanism of lithium responsiveness in BD. Larger sample size studies are necessary to determine its utility.

Brain-wide activation involved in 15 mA transcranial alternating current stimulation in patients with first-episode major depressive disorder.

Background: Although 15 mA transcranial alternating current stimulation (tACS) has a therapeutic effect on depression, the activations of brain structures in humans accounting for this tACS configuration remain largely unknown. Aims: To investigate which intracranial brain structures are engaged in the tACS at 77.5 Hz and 15 mA, delivered via the forehead and the mastoid electrodes in the human brain. Methods: Actual human head models were built using the magnetic resonance imagings of eight outpatient volunteers with drug-naïve, first-episode major depressive disorder and then used to perform the electric field distributions with SimNIBS software. Results: The electric field distributions of the sagittal, coronal and axial planes showed that the bilateral frontal lobes, bilateral temporal lobes, hippocampus, cingulate, hypothalamus, thalamus, amygdala, cerebellum and brainstem were visibly stimulated by the 15 mA tACS procedure. Conclusions: Brain-wide activation, including the cortex, subcortical structures, cerebellum and brainstem, is involved in the 15 mA tACS intervention for first-episode major depressive disorder. Our results indicate that the simultaneous involvement of multiple brain regions is a possible mechanism for its effectiveness in reducing depressive symptoms.

Efficacy and Safety of Antidiabetic Agents for Major Depressive Disorder and Bipolar Depression: A Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials.

BACKGROUND: This meta-analysis aimed to determine the efficacy and safety of antidiabetic agents in the treatment of major depressive disorder and bipolar depression. METHODS: Randomized controlled trials (RCTs) of antidiabetic agents in major depressive disorder or bipolar depression were searched in three electronic databases and three clinical trial registry websites from their inception up to October 2023. The differences in changes in the depression rating scale scores from baseline to endpoint or pre-defined sessions, response rate, remission rate, rate of side effects and dropout rate between antidiabetic agents and placebo were meta-analyzed. RESULTS: Six RCTs involving 399 participants were included in the final meta-analysis, which did not find that antidiabetics outperformed the placebo in reducing depressive symptoms. The standardized mean difference (SMD) in the depression scores from baseline to endpoint was 0.25 (95% CI -0.1, 0.61). However, a subgroup analysis found a significant difference between antidiabetics and placebos in reducing depressive symptoms in Middle Eastern populations, with an SMD of 0.89 (95% CI 0.44, 1.34). CONCLUSIONS: The current meta-analysis does not support the efficacy of antidiabetics being superior to the placebo in the treatment of unipolar and bipolar depression. However, a subgroup analysis indicates that patients from the Middle East may benefit from adding an antidiabetic medication to their ongoing medication(s) for their depression. Larger studies with good-quality study designs are warranted.

Evidence of a large current of transcranial alternating current stimulation directly to deep brain regions.

Deep brain regions such as hippocampus, insula, and amygdala are involved in neuropsychiatric disorders, including chronic insomnia and depression. Our recent reports showed that transcranial alternating current stimulation (tACS) with a current of 15 mA and a frequency of 77.5 Hz, delivered through a montage of the forehead and both mastoids was safe and effective in intervening chronic insomnia and depression over 8 weeks. However, there is no physical evidence to support whether a large alternating current of 15 mA in tACS can send electrical currents to deep brain tissue in awake humans. Here, we directly recorded local field potentials (LFPs) in the hippocampus, insula and amygdala at different current strengths (1 to 15 mA) in 11 adult patients with drug-resistant epilepsy implanted with stereoelectroencephalography (SEEG) electrodes who received tACS at 77.5 Hz from 1 mA to 15 mA at 77.5 Hz for five minutes at each current for a total of 40 min. For the current of 15 mA at 77.5 Hz, additional 55 min were applied to add up a total of 60 min. Linear regression analysis revealed that the average LFPs for the remaining contacts on both sides of the hippocampus, insula, and amygdala of each patient were statistically associated with the given currents in each patient (p < 0.05-0.01), except for the left insula of one subject (p = 0.053). Alternating currents greater than 7 mA were required to produce significant differences in LFPs in the three brain regions compared to LFPs at 0 mA (p < 0.05). The differences remained significant after adjusting for multiple comparisons (p < 0.05). Our study provides direct evidence that the specific tACS procedures are capable of delivering electrical currents to deep brain tissues, opening a realistic avenue for modulating or treating neuropsychiatric disorders associated with hippocampus, insula, and amygdala.

Comprehensive Analysis of Electronic Health Records to Characterize The Association Between Intimate Partner Violence and Mental Health.

Intimate partner violence (IPV) involves physical, emotional, and sexual harm to the survivor. To characterize the relationship between mental health and IPV, we utilized electronic health records (EHR) data from IBM Explorys. Focusing on 15 mental health conditions and IPV, we queried cohorts of patients with these conditions to discover additional medical terms, including symptoms, findings, and diagnoses that are prevalent in these cohorts. We then systematically assessed the (i) direct association (co-occurrence, i.e., relative prevalence of a medical term in a cohort compared to the background population) and (ii) indirect association (the similarity between co-occurrence profiles) between all pairs of these mental health conditions. Our results showed that direct and indirect measures of association provide complementary insights into the relationship between pairs of conditions. Using this framework, we discovered several patterns of association among 16 different mental health related conditions.

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Differences in intracellular protein levels in monocytes and CD4+ lymphocytes between bipolar depressed patients and healthy controls: A pilot study with tyramine-based signal-amplified flow cytometry.

BACKGROUND: Molecular biomarkers for bipolar disorder (BD) that distinguish it from other manifestations of depressive symptoms remain unknown. The aim of this study was to determine if a very sensitive tyramine-based signal-amplification technology for flow cytometry (CellPrint™) could facilitate the identification of cell-specific analyte expression profiles of peripheral blood cells for bipolar depression (BPD) versus healthy controls (HCs). METHODS: The diagnosis of psychiatric disorders was ascertained with Mini International Neuropsychiatric Interview for DSM-5. Expression levels for eighteen protein analytes previously shown to be related to bipolar disorder were assessed with CellPrint™ in CD4+ T cells and monocytes of bipolar patients and HCs. Implementation of protein-protein interaction (PPI) network and pathway analysis was subsequently used to identify new analytes and pathways for subsequent interrogations. RESULTS: Fourteen drug-naïve or -free patients with bipolar I or II depression and 17 healthy controls (HCs) were enrolled. The most distinguishable changes in analyte expression based on t-tests included GSK3ß, HMGB1, IRS2, phospho-GSK3αß, phospho-RELA, and TSPO in CD4+ T cells and calmodulin, GSK3ß, IRS2, and phospho-HS1 in monocytes. Subsequent PPI and pathway analysis indicated that prolactin, leptin, BDNF, and interleukin-3 signal pathways were significantly different between bipolar patients and HCs. LIMITATION: The sample size of the study was small and 2 patients were on medications. CONCLUSION: In this pilot study, CellPrint™ was able to detect differences in cell-specific protein levels between BPD patients and HCs. A subsequent study including samples from patients with BPD, major depressive disorder, and HCs is warranted.

Divergent Directionality of Immune Cell-Specific Protein Expression between Bipolar Lithium Responders and Non-Responders Revealed by Enhanced Flow Cytometry.

Background and Objectives: There is no biomarker to predict lithium response. This study used CellPrint™ enhanced flow cytometry to study 28 proteins representing a spectrum of cellular pathways in monocytes and CD4+ lymphocytes before and after lithium treatment in patients with bipolar disorder (BD). Materials and Methods: Symptomatic patients with BD type I or II received lithium (serum level ≥ 0.6 mEq/L) for 16 weeks. Patients were assessed with standard rating scales and divided into two groups, responders (≥50% improvement from baseline) and non-responders. Twenty-eight intracellular proteins in CD4+ lymphocytes and monocytes were analyzed with CellPrint™, an enhanced flow cytometry procedure. Data were analyzed for differences in protein expression levels. Results: The intent-to-treat sample included 13 lithium-responders (12 blood samples before treatment and 9 after treatment) and 11 lithium-non-responders (11 blood samples before treatment and 4 after treatment). No significant differences in expression between the groups was observed prior to lithium treatment. After treatment, the majority of analytes increased expression in responders and decreased expression in non-responders. Significant increases were seen for PDEB4 and NR3C1 in responders. A significant decrease was seen for NR3C1 in non-responders. Conclusions: Lithium induced divergent directionality of protein expression depending on the whether the patient was a responder or non-responder, elucidating molecular characteristics of lithium responsiveness. A subsequent study with a larger sample size is warranted.

Transcranial alternating current stimulation for treating depression: a randomized controlled trial.

Treatment of depression with antidepressants is partly effective. Transcranial alternating current stimulation can provide a non-pharmacological alternative for adult patients with major depressive disorder. However, no study has used the stimulation to treat first-episode and drug-naïve patients with major depressive disorder. We used a randomized, double-blind, sham-controlled design to examine the clinical efficacy and safety of the stimulation in treating first-episode drug-naïve patients in a Chinese Han population. From 4 June 2018 to 30 December 2019, 100 patients were recruited and randomly assigned to receive 20 daily 40-min, 77.5 Hz, 15 mA, one forehead and two mastoid sessions of active or sham stimulation (n = 50 for each group) in four consecutive weeks (Week 4), and were followed for additional 4-week efficacy/safety assessment without stimulation (Week 8). The primary outcome was a remission rate defined as the 17-item Hamilton Depression Rating Scale (HDRS-17) score ≤ 7 at Week 8. Secondary analyses were response rates (defined as a reduction of ≥ 50% in the HDRS-17), changes in depressive symptoms and severity from baseline to Week 4 and Week 8, and rates of adverse events. Data were analysed in an intention-to-treat sample. Forty-nine in the active and 46 in the sham completed the study. Twenty-seven of 50 (54%) in the active treatment group and 9 of 50 (18%) in the sham group achieved remission at the end of Week 8. The remission rate was significantly higher in the active group compared to that in the sham group with a risk ratio of 1.78 (95% confidence interval, 1.29, 2.47). Compared with the sham, the active group had a significantly higher remission rate at Week 4, response rates at Weeks 4 and 8, and a larger reduction in depressive symptoms from baseline to Weeks 4 and 8. Adverse events were similar between the groups. In conclusion, the stimulation on the frontal cortex and two mastoids significantly improved symptoms in first-episode drug-naïve patients with major depressive disorder and may be considered as a non-pharmacological intervention for them in an outpatient setting.

Protein Biomarkers in Monocytes and CD4+ Lymphocytes for Predicting Lithium Treatment Response of Bipolar Disorder: a Feasibility Study with Tyramine-Based Signal-Amplified Flow Cytometry.

Purpose: To determine if enhanced flow cytometry (CellPrint™) can identify intracellular proteins of lithium responsiveness in monocytes and CD4+ lymphocytes from patients with bipolar disorder. Methods: Eligible bipolar I or II patients were openly treated with lithium for 16-weeks. Baseline levels of Bcl2, BDNF, calmodulin, Fyn, phospho-Fyn/phospho-Yes, GSK3ß, phospho-GSK3αß, HMGB1, iNOS, IRS2, mTor, NLPR3, PGM1, PKA C-α, PPAR-γ, phospho-RelA, and TPH1 in monocytes and CD4+ lymphocytes of lithium responders and non-responders were measured with CellPrint™. Their utility of discriminating responders from non-responders was explored. Protein-protein network and pathway enrichment analyses were conducted. Results: Of the 24 intent-to-treat patients, 12 patients completed the 16-week study. Eleven of 13 responders and 8 of 11 non-responders were available for this analysis. The levels of the majority of analytes in lithium responders were lower than non-responders in both cell types, but only the level of GSK3ß in monocytes was significantly different (p = 0.034). The combination of GSK3ß and phospho-GSK3αß levels in monocytes correctly classified 11/11 responders and 5/8 non-responders. Combination of GSK3ß, phospho-RelA, TPH1 and PGM1 correctly classified 10/11 responders and 6/7 non-responders, both with a likelihood of ≥ 85%. Prolactin, leptin, BDNF, neurotrophin, and epidermal growth factor/epidermal growth factor receptor signaling pathways are involved in the lithium treatment response. GSK3ß and RelA genes are involved in 4 of 5 these pathways. Conclusion: CellPrint™ flow cytometry was able to detect differences in multiple proteins in monocytes and CD4+ lymphocytes between lithium responders and non-responders. A large study is warranted to confirm or refute these findings.

Cingulum bundle connectivity in treatment-refractory compared to treatment-responsive patients with bipolar disorder and healthy controls: a tractography and surgical targeting analysis.

OBJECTIVE: The clinical response of patients with bipolar disorder to medical treatment is variable. A better understanding of the underlying neural circuitry involved in bipolar treatment responsivity subtypes may provide insight into treatment resistance and aid in identifying an effective surgical target for deep brain stimulation (DBS) specific to the disorder. Despite considerable imaging research related to the disease, a paucity of comparative imaging analyses of treatment responsiveness exists. There are also no DBS targets designed expressly for patients with bipolar disorder. Therefore, the authors analyzed cingulum bundle axonal connectivity in relation to cortico-striatal-thalamo-cortical (CSTC) loops implicated in bipolar disorder across subjects who are responsive to treatment (RSP) and those who are refractory to therapy (REF), compared to healthy controls (HCs). METHODS: Twenty-five subjects with bipolar disorder (13 RSP and 12 REF), diagnosed using the Mini International Neuropsychiatric Interview and classified with standardized rating scales, and 14 HCs underwent MRI with diffusion sequences for probabilistic diffusion-weighted tractography analysis. Image processing and tractography were performed using MRTrix. Region of interest (ROI) masks were created manually for 10 anterior cingulum bundle subregions, including surgical targets previously evaluated for the treatment of bipolar disorder (cingulotomy and subgenual cingulate DBS targets). Cortical and subcortical ROIs of brain areas thought to be associated with bipolar disorder and described in animal tract-tracing models were created via FreeSurfer. The number of axonal projections from the cingulum bundle subregion ROIs to cortical/subcortical ROIs for each group was compared. RESULTS: Significant differences were found across groups involving cingulum bundle and CSTC loops. Subjects in the RSP group had increased connections from rostral cingulum bundle to medial orbitofrontal cortex, which is part of the limbic CSTC loop, whereas subjects in the REF group had increased connectivity from rostral cingulum bundle to thalamus. Additionally, compared to HCs, both RSP and REF subjects had decreased cingulum bundle dorsal connectivity (dorsal anterior/posterior cingulate, dorsomedial/lateral frontal cortex) and increased cingulum bundle ventral connectivity (subgenual cingulate, frontal pole, lateral orbitofrontal cortex) involving limbic and associative CSTC loops. CONCLUSIONS: Findings demonstrate that bipolar treatment responsivity may be associated with significant differences in cingulum bundle connectivity in relation to CSTC loops, which may help identify a surgical target for bipolar disorder treatment via DBS in the future.

Associations Among Irritability, High-Sensitivity C-Reactive Protein/Interleukin-6, and Depression in Patients With Early-Stage Breast Cancer Undergoing Chemotherapy: A Prospective Study.

BACKGROUND: Association between irritability and depression has been frequently reported, but the nature of this association in the adult population is poorly understood. OBJECTIVES: We examined associations among irritability (e.g., a feeling of agitation), inflammatory biomarkers, and depression during chemotherapy. METHODS: Forty-four patients with nonmetastatic breast cancer were assessed at baseline and after 3 months of chemotherapy on The Irritability Scale-Initial Version, severity and new onset of depressive symptoms using the Hamilton Depression Rating Scale, and serum levels of high-sensitivity C-reactive protein and interleukin 6. RESULTS: At baseline, high-sensitivity C-reactive protein significantly correlated with physical and mood subscales of The Irritability Scale-Initial Version, but not with depression. Irritability and high-sensitivity C-reactive protein significantly predicted the severity and new onset of moderate to severe depressive symptoms over time, while irritability and interleukin 6 significantly predicted new onset of moderate to severe depressive symptoms. CONCLUSION: The findings suggest that irritability is an independent risk factor of depression and associated with increasing high-sensitivity C-reactive protein. Irritability needs to be effectively managed in patients with cancer undergoing chemotherapy to prevent them from developing depressive symptoms. These preliminary findings should be investigated in future large-sample studies.

Correction of depression-associated circadian rhythm abnormalities is associated with lithium response in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is characterized by episodes of depression and mania and disrupted circadian rhythms. Lithium is an effective therapy for BD, but only 30%-40% of patients are fully responsive. Preclinical models show that lithium alters circadian rhythms. However, it is unknown if the circadian rhythm effects of lithium are essential to its therapeutic properties. METHODS: In secondary analyses of a multi-center, prospective, trial of lithium for BD, we examined the relationship between circadian rhythms and therapeutic response to lithium. Using standardized instruments, we measured morningness, diurnal changes in mood, sleep, and energy (circadian rhythm disturbances) in a cross-sectional study of 386 BD subjects with varying lithium exposure histories. Next, we tracked symptoms of depression and mania prospectively over 12 weeks in a subset of 88 BD patients initiating treatment with lithium. Total, circadian, and affective mood symptoms were scored separately and analyzed. RESULTS: Subjects with no prior lithium exposure had the most circadian disruption, while patients stable on lithium monotherapy had the least. Patients who were stable on lithium with another drug or unstable on lithium showed intermediate levels of disruption. Treatment with lithium for 12 weeks yielded significant reductions in total and affective depression symptoms. Lithium responders (Li-Rs) showed improvement in circadian symptoms of depression, but non-responders did not. There was no difference between Li-Rs and nonresponders in affective, circadian, or total symptoms of mania. CONCLUSIONS: Exposure to lithium is associated with reduced circadian disruption. Lithium response at 12 weeks was selectively associated with the reduction of circadian depressive symptoms. We conclude that stabilization of circadian rhythms may be an important feature of lithium's therapeutic effects. CLINICAL TRIALS REGISTRY: NCT0127253.

Image restoration for real-world under-display imaging.

Under-display imaging technique was recently proposed to enlarge the screen-to-body ratio for full-screen devices. However, existing image restoration algorithms have difficulty generalizing to real-world under-display (UD) images, especially to images containing strong light sources. To address this issue, we propose a novel method for building a synthetic dataset (CalibPSF dataset) and introduce a two-stage neural network to solve the under-display imaging degradation problem. The CalibPSF dataset is generated using the calibrated high dynamic range point spread function (PSF) of the under-display optical system and contains various simulated light sources. The two-stage network solves the color distortion and diffraction degradation in order. We evaluate the performance of our algorithm on our captured real-world test set. Comprehensive experiments demonstrate the superiority of our method in different dynamic range scenes.

Illness stage and predominant polarity in bipolar disorder: Correlation with burden of illness and moderation of treatment outcome.

Bipolar disorder often follows a set progression best described in stages where advanced stages are associated with poorer outcomes. Bipolar disorder is also often characterized by a predominance of episode polarity, where some individuals experience more depressive episodes (termed predominant depressive polarity) while others experience more hypo/manic episodes (termed predominant hypo/manic polarity). We examined the associations between staging and predominant polarity with measures of illness burden and treatment outcome utilizing data from a six-month comparative effectiveness trial of lithium and quetiapine in bipolar disorder (Bipolar CHOICE). We used number of self-reported lifetime mood (depressive and hypo/manic) episodes as a proxy for staging and ratio of depressive to manic episodes to define predominant polarity. Polarity and staging were correlated with several measures of burden of illness. Childhood abuse was correlated with more lifetime mood episodes, while more depressive episodes and depressive polarity were correlated with more anxiety disorder comorbidity. Depressive polarity was also correlated with more past trials of psychotropics, particularly antidepressants. However, neither staging nor predominant polarity moderated the randomized treatment effect of lithium vs. quetiapine. Number of depressive episodes in the past year was identified as a potential predictor of overall worse treatment outcome, regardless of medication condition. In conclusion, though staging and predominant episode polarity correlated with several measures of illness burden, they were not associated with differential treatment outcomes. This could be because many of our patients presented for treatment at advanced stages of illness and further highlights the need for early intervention in bipolar disorder.

Efficacy and safety of electroconvulsive therapy plus medication versus medication alone in acute mania: A meta-analysis of randomized controlled trials.

Although some studies have reported the potential efficacy of electroconvulsive therapy (ECT) in the treatment of acute mania, there is no consensus on the matter. Therefore, we performed a meta-analysis to determine the efficacy and safety of ECT combination with medication (ECT-combo) vs. medication alone (Med-alone) in the treatment of acute mania. Randomized controlled trials (RCTs) of ECT-combo versus Med-alone in acute mania were searched in Chinese databases and English databases from their inceptions up to February 2020. Twelve RCTs (including 863 patients, n=863) met our criteria and were included into meta-analysis. The pooled results found that ECT-combo outperformed Med-alone in reducing manic symptoms from baseline to endpoint with a standardized mean difference of -3.50 (95% CI: -4.57, -2.44, p<0.00001). The significant difference occurred after 3-5 treatments or after a 1-week treatment. ECT-combo had significantly increased memory impairment compared to Med-alone. Apart from increased memory impairment in ECT-combo group (SMD=8.33; 95% CI: 2.73 to 25.45, p= 0.0002), no other statistically significant differences in side effects or drop-out rates were found between groups. The results of this meta-analysis suggest that ECT-combo was significantly superior to Med-alone in efficacy and well-tolerated as Med-alone in the acute treatment of mania. However, larger studies with randomized, double-blind design, and standardized treatment regimens are still warranted due to the high heterogeneity of studies included in the present meta-analysis.

Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study.

BACKGROUND: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. METHODS: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. RESULTS: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. CONCLUSIONS: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

Safety and Tolerability of Both Arm Ischemic Conditioning in Patients With Major Depression: A Proof of Concept Study.

PURPOSE: A substantial proportion of patients with major depressive disorder (MDD) does not respond or cannot tolerate to currently available treatments. This study was to assess the safety and tolerability of Remote Limb Ischemic Preconditioning (RLIPC) as an adjunctive therapy in patients with MDD. PATIENTS AND METHODS: Enrolled patients underwent RLIPC, five cycles of simultaneous bilateral arm ischemia, 5 min and followed by reperfusion of each cycle, and once daily for eight consecutive weeks. Depression and anxiety severity, and quality of life were assessed every 2 weeks. Descriptive analysis was used for safety and tolerability data. RESULTS: Thirty-seven participants completed at least one RLIPC. Twenty-four of them (64.9%) completed the study. Twelve patients prematurely discontinued the study due to poor adherence, and one due to a mild side effect. The changes in HRSD-17, GAD-7 and QOL-6 total scores from baseline to the endpoint were significant from the end of second week treatment onwards. The responder and remission rates were 59.46% (22/37) and 54.05% (20/37) at the endpoint, respectively. CONCLUSION: RLIPC was safe and well tolerated, and may be effective in reducing depressive symptoms in patients with MDD. Large studies are warranted to test its efficacy and safety as monotherapy or adjunctive therapy in the treatment of MDD.

Sequential Multiple Assignment Randomized Treatment (SMART) for Bipolar Disorder at Any Phase of Illness and at least Mild Symptom Severity.

Objectives: To sequentially study the effectiveness of lithium and divalproex monotherapy and adjunctive therapy with quetiapine or lamotrigine in the acute and continuation treatment of bipolar I or II disorder at any phase of illness and at least mild symptom severity. Methods: From June 2011 to December 2016, patients with bipolar I or II disorder (using DSM-IV diagnostic criteria) and CGI-S (Clinical Global Impression-Severity) ⩾ 3 were randomized to receive lithium or divalproex monotherapy for 2 weeks. Patients who had CGI-S-depression ⩾ 3 for 2 weeks at any time after 2-week monotherapy were randomly assigned to receive quetiapine or lamotrigine, or remaining on monotherapy for a total of 26 weeks. Results: The rates of early termination due to lack of efficacy and side effects and changes in BISS (Bipolar Inventory of Symptoms Scale) and CGI-S total score were not significantly different between lithium and divalproex. The completion rate was significantly higher with adjunctive therapy than with monotherapy. BISS and CGI-S total scores, and their sub-scores were significantly reduced with adjunctive therapy compared to monotherapy. Adjunctive therapy significantly increased survival times compared to monotherapy (hazard ratio = 6.8), and the monotherapy group had a significantly increased risk for not reaching sustained recovery from depression (hazard ratio = 12.7). Patients who did not need the 2nd randomization and remained on monotherapy had a significantly reduced hazard for discontinuation (hazard ratio = 3.8). Conclusions: The efficacy of lithium and divalproex as monotherapy was modest. Adjunctive lamotrigine and quetiapine to either one was well-tolerated and equally effective in reducing bipolar symptomatology, but adjunctive therapy should be initiated as early as possible when depression symptoms are present.