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Genes associated with risk for bipolar disorder have been searched with candidate gene and genome-wide association approaches.3,4 Most findings from these methods have not been replicated.3 However, the most consistent associations were observed for several candidate genes which included SLC6A4/5-HTT, BDNF, COMT, DISC1, DTNBP1, DAOA, and NRG1.3 By contrast, two genes, CACNA1C and ANK3, have been replicated for the association with risk for bipolar disorder in most genome-wide association studies (GWAS).3,4 Similar to the studies of bipolar disorder risk genes, most genes related to lithium treatment response have not been replicated in candidate gene studies and GWAS.5-7 In The Lancet, Liping Hou and colleagues,8 from the International Consortium on Lithium Genetics, provide intriguing data from a large GWAS of lithium responders versus non-responders.

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.

Bipolar disorders are chronic and recurrent disorders that affect >1% of the global population. Bipolar disorders are leading causes of disability in young people as they can lead to cognitive and functional impairment and increased mortality, particularly from suicide and cardiovascular disease. Psychiatric and nonpsychiatric medical comorbidities are common in patients and might also contribute to increased mortality. Bipolar disorders are some of the most heritable psychiatric disorders, although a model with gene–environment interactions is believed to best explain the aetiology. Early and accurate diagnosis is difficult in clinical practice as the onset of bipolar disorder is commonly characterized by nonspecific symptoms, mood lability or a depressive episode, which can be similar in presentation to unipolar depression. Moreover, patients and their families do not always understand the significance of their symptoms, especially with hypomanic or manic symptoms. As specific biomarkers for bipolar disorders are not yet available, careful clinical assessment remains the cornerstone of diagnosis. The detection of hypomanic symptoms and longtudinal clinical assessment are crucial to differentiate a bipolar disorder from other conditions. Optimal early treatment of patients with evidence-based medication (typically mood stabilizers and antipsychotics) and psychosocial strategies is necessary. Bipolar disorders are characterized by acute episodes of mania or hypomania and depression. Psychosis can occur in some patients, and cognitive symptoms, including deficits in executive function and memory, are frequent. In this Primer, Vieta et al. discuss the epidemiology, mechanisms, diagnosis and management of bipolar disorders.

The National Institute of Mental Health (NIMH) ‘fast-fail’ approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n  = 45) and placebo ( n  = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F (1,86) = 5.58, P  < 0.01; effect size = 0.58 (95% confidence interval, 0.13–0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the ‘fast-fail’ approach. A phase 2 proof-of-mechanism trial shows that a κ-opioid receptor antagonist improves reward-related functioning in the brain and a clinical measure of anhedonia in patients with mood and anxiety disorders, serving as a model for implementing the ‘fast-fail’ approach to psychiatric treatment development.

Objective Depression is one of the most common mental disorders in the United States in both civilian and military populations, but few prospective studies assess a wide range of predictors across multiple domains for new‐onset (incident) depression in adulthood. Supervised machine learning methods can identify predictors of incident depression out of many different candidate variables, without some of the assumptions and constraints that underlie traditional regression analyses. The objectives of this study were to identify predictors of incident depression across 5 years of follow‐up using machine learning, and to assess prediction accuracy of the algorithms. Methods Data were from a cohort of Army National Guard members free of history of depression at baseline (n = 1951 men and 298 women), interviewed once per year for probable depression. Classification trees and random forests were constructed and cross‐validated, using 84 candidate predictors from the baseline interviews. Results Stressors and traumas such as emotional mistreatment and adverse childhood experiences, demographics such as being a parent or student, and military characteristics including paygrade and deployment location were predictive of probable depression. Cross‐validated random forest algorithms were moderately accurate (68% for women and 73% for men). Conclusions Events and characteristics throughout the life course, both in and outside of deployment, predict incident depression in adulthood among military personnel. Although replication studies are needed, these results may help inform potential intervention targets to reduce depression incidence among military personnel. Future research should further refine and explore interactions between identified variables. HIGHLIGHTS In a cohort study of U.S. Army National Guard personnel, we found that stressors and traumas such as emotional mistreatment and adverse childhood experiences, demographics such as being a parent or student, and military characteristics including paygrade and deployment location were predictive of new‐onset depression. Cross‐validated random forest algorithms were moderately accurate for predicting depression. Among military personnel, events and characteristics throughout the life course—in and outside of deployment—predict new‐onset depression in adulthood.

This review focused on the treatment-emergent mania/hypomania (TEM) associated with repetitive transcranial magnetic stimulation (rTMS) treatment of depression. English-language literature published from 1966–2006 and indexed in Medline was searched. Ten of 53 randomized controlled trials on rTMS treatment of depression specifically addressed TEM. The pooled TEM rate is 0.84% for the active treatment group and 0.73% for the sham group. The difference is not statistically significant. Along with case reports, a total of 13 cases of TEM associated with rTMS treatment of depression have been published. Most of these patients were diagnosed with bipolar disorder and the majority of patients experiencing TEM took medication concurrent with rTMS. The parameters of rTMS used in these cases were scattered over the spectrum of major parameters explored in previous studies. Most train durations and intervals were within the published safety guidelines of the field. Reducing the frequency of sessions from two per day to one per day might be associated with a lower likelihood of TEM recurrence. The severity of manic symptoms varied significantly, but all cases responded to treatment that included a decrease or discontinuation of antidepressant and/or rTMS treatment and/or use of anti-manic medication. Current data suggests that rTMS treatment carries a slight risk of TEM that is not statistically higher than that associated with sham treatment. More systematic studies are needed to better understand TEM associated with rTMS. Special precautions and measures should be adopted to prevent, monitor, and manage TEM in research and practice.

A neuronal model of bipolar disorder based on induced pluripotent stem cell (iPSC) technology finds hyperactive action-potential firing and differential responsiveness to lithium in iPSC-derived neurons from patients with bipolar disorder. Efficacy of lithium in bipolar disorder Lithium is widely used as a mood stabilizer in bipolar disorder, but not all patients respond favourably. In this paper, Fred Gage and colleagues generated hippocampal dentate gyrus-like neurons from induced pluripotent stem cells (iPSCs) obtained from lithium-responsive and lithium-non-responsive patients with bipolar disorder in order to assess differences in cellular phenotypes. They found mitochondrial abnormalities and hyperexcitability in young iPSC-derived neurons from bipolar disorder patients. Hyperexcitability was reversed by lithium treatment only in neurons derived from lithium-responsive individuals. This suggests that hyperexcitability may be an early endophenotype of bipolar disorder and that iPSC models may be useful for the development of new therapies. Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide 1 . Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity 2 . Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models 3 , such as reduced glial cell number in the prefrontal cortex of patients 4 , upregulated activities of the protein kinase A and C pathways 5 , 6 , 7 and changes in neurotransmission 8 , 9 , 10 , 11 . However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca 2+ imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.

There is uncertainty about the efficacy of lamotrigine in bipolar depressive episodes. To synthesise the evidence for the efficacy of lamotrigine in bipolar depressive episodes. Systematic review and meta-analysis of individual patient data from randomised controlled trials comparing lamotrigine with placebo. Individual data from 1072 participants from five randomised controlled trials were obtained. More individuals treated with lamotrigine than placebo responded to treatment on both the Hamilton Rating Scale for Depression (HRSD) (relative risk (RR)=1.27, 95% CI 1.09-1.47, P=0.002) and Montgomery-Asberg Depression Rating Scale (MADRS) (RR=1.22, 95% CI 1.06-1.41, P=0.005). There was an interaction (P=0.04) by baseline severity of depression: lamotrigine was superior to placebo in people with HRSD score >24 (RR=1.47, 95% CI 1.16-1.87, P=0.001) but not in people with HRSD score < or =24 (RR=1.07, 95% CI 0.90-1.27, P=0.445). There is consistent evidence that lamotrigine has a beneficial effect on depressive symptoms in the depressed phase of bipolar disorder. The overall pool effect was modest, although the advantage over placebo was larger in more severely depressed participants.

Anhedonia remains a major clinical issue for which there is few effective interventions. Untreated or poorly controlled anhedonia has been linked to worse disease course and increased suicidal behavior across disorders. Taking a proof-of-mechanism approach under the auspices of the National Institute of Mental Health FAST-FAIL initiative, we were the first to show that, in a transdiagnostic sample screened for elevated self-reported anhedonia, 8 weeks of treatment with a kappa-opioid receptor (KOR) antagonist resulted in significantly higher reward-related activation in one of the core hubs of the brain reward system (the ventral striatum), better reward learning in the Probabilistic Reward Task (PRT), and lower anhedonic symptoms, relative to 8 weeks of placebo. Here, we performed secondary analyses of the PRT data to investigate the putative effects of KOR antagonism on anhedonic behavior with more precision by using trial-level model-based Bayesian computational modeling and probability analyses. We found that, relative to placebo, KOR antagonism resulted in significantly higher learning rate (i.e., ability to learn from reward feedback) and a more sustained preference toward the more frequently rewarded stimulus, but unaltered reward sensitivity (i.e., the hedonic response to reward feedback). Collectively, these findings provide novel evidence that in a transdiagnostic sample characterized by elevated anhedonia, KOR antagonism improved the ability to modulate behavior as a function of prior rewards. Together with confirmation of target engagement in the primary report (Krystal et al., Nat Med, 2020), the current findings suggest that further transdiagnostic investigation of KOR antagonism for anhedonia is warranted.

BackgroundThe long-acting injectable antipsychotic aripiprazole once-monthly 400 mg (AOM 400) was recently approved for maintenance treatment of bipolar I disorder (BP-I). The purpose of this study was to evaluate the safety, tolerability, and efficacy of AOM 400 as long-term maintenance treatment for BP-I.MethodsThis open-label multicenter study evaluated the effectiveness of AOM 400 as maintenance treatment for BP-I by assessing safety and tolerability (primary objective) and efficacy (secondary objective). The study enrolled AOM 400-naive (“de novo”) patients as well as AOM 400-experienced (“rollover”) patients with BP-I from a lead-in randomized, placebo-controlled clinical trial that demonstrated the efficacy of AOM 400 in the maintenance treatment of BP-I (Calabrese et al. in J Clin Psychiatry 78:324–331, 2017). Safety variables included frequency and severity of treatment-emergent adverse events (TEAEs) and TEAEs resulting in study discontinuation. Efficacy was assessed by the proportion of patients maintaining stability throughout the maintenance phase, as well as mean changes from baseline in Young Mania Rating Scale (YMRS), Montgomery–Asberg Depression Rating Scale, and Clinical Global Impressions for Bipolar Disorder–Severity of Illness Scale (CGI-BP-S) total scores. Patient acceptability and tolerability of treatment was assessed using the Patient Satisfaction with Medication Questionnaire-Modified.ResultsOf 464 patients entering the maintenance phase, 379 (82%) were de novo and 85 (18%) were rollover. TEAEs were more common in de novo than rollover patients. The overall discontinuation rate due to TEAEs was 10.3% (48/464). Improvements in YMRS and CGI-BP-S total scores were maintained during the study, and the vast majority of both de novo (87.0%) and rollover (97.6%) patients maintained stability through their last visit. Overall, the need for rescue medication during the maintenance phase was minimal (< 10% of patients). Patient satisfaction levels were high, with both de novo and rollover patients rating the side effect burden of AOM 400 as greatly improved relative to previous medications.ConclusionAOM 400 was safe, effective, and well tolerated by both de novo and AOM 400-experienced patients with BP-I for long-term maintenance treatment.Trial registration ClinicalTrials.gov, NCT01710709