AbstractBipolar disorders (BDs) are recurrent and sometimes chronic disorders of mood that affect around 2% of the world’s population and encompass a spectrum between severe elevated and excitable ...mood states (mania) to the dysphoria, low energy, and despondency of depressive episodes. The illness commonly starts in young adults and is a leading cause of disability and premature mortality. The clinical manifestations of bipolar disorder can be markedly varied between and within individuals across their lifespan. Early diagnosis is challenging and misdiagnoses are frequent, potentially resulting in missed early intervention and increasing the risk of iatrogenic harm. Over 15 approved treatments exist for the various phases of bipolar disorder, but outcomes are often suboptimal owing to insufficient efficacy, side effects, or lack of availability. Lithium, the first approved treatment for bipolar disorder, continues to be the most effective drug overall, although full remission is only seen in a subset of patients. Newer atypical antipsychotics are increasingly being found to be effective in the treatment of bipolar depression; however, their long term tolerability and safety are uncertain. For many with bipolar disorder, combination therapy and adjunctive psychotherapy might be necessary to treat symptoms across different phases of illness. Several classes of medications exist for treating bipolar disorder but predicting which medication is likely to be most effective or tolerable is not yet possible. As pathophysiological insights into the causes of bipolar disorders are revealed, a new era of targeted treatments aimed at causal mechanisms, be they pharmacological or psychosocial, will hopefully be developed. For the time being, however, clinical judgment, shared decision making, and empirical follow-up remain essential elements of clinical care. This review provides an overview of the clinical features, diagnostic subtypes, and major treatment modalities available to treat people with bipolar disorder, highlighting recent advances and ongoing therapeutic challenges.
Although genetic studies of Bipolar Disorder have been pursued for decades, it has only been in the last several years that clearly replicated findings have emerged. These findings, typically of ...modest effects, point to a polygenic genetic architecture consisting of multiple common and rare susceptibility variants. While larger genome-wide association studies are ongoing, the advent of whole exome and genome sequencing should lead to the identification of rare, and potentially more penetrant, variants. Progress along both fronts will provide novel insights into the biology of Bipolar Disorder and help usher in a new era of personalized medicine and improved treatments.
Accumulating evidence indicates that DNA copy number variation (CNV) is likely to make a significant contribution to human diversity and also play an important role in disease susceptibility. Recent ...advances in genome sequencing technologies have enabled the characterization of a variety of genomic features, including CNVs. This has led to the development of several bioinformatics approaches to detect CNVs from next-generation sequencing data. Here, we review recent advances in CNV detection from whole genome sequencing. We discuss the informatics approaches and current computational tools that have been developed as well as their strengths and limitations. This review will assist researchers and analysts in choosing the most suitable tools for CNV analysis as well as provide suggestions for new directions in future development.
The course of Bipolar Disorder (BD) is highly variable, with marked inter and intra-individual differences in symptoms and functioning. In this study, we identified illness trajectories across major ...clinical domains that could have etiological, prognostic, and therapeutic relevance.
Using the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, we performed univariate and multivariate trajectory modeling of depressive symptoms, manic symptoms, and psychosocial functioning. Multinomial regression was performed to identify baseline variables associated with poor outcome trajectories.
Depressive symptoms predominated, with most subjects being found in trajectories characterized by various degrees of depressive symptoms and 13% of subjects being classified in a poor outcome 'persistently depressed' trajectory. Most subjects experienced few manic symptoms, although approximately 10% of subjects followed a trajectory of persistently manic symptoms. Trajectory analysis of psychosocial functioning showed impairment in most of the sample, with little improvement during follow up. Multi-trajectory analyses highlighted significant impairment in subjects with persistently mixed and persistently depressed trajectories of illness. In general, poor outcome trajectories were marked by lower educational attainment, higher unemployment and disability, and a greater likelihood of adverse clinical features (rapid cycling and suicide attempts) and comorbid diagnoses (anxiety disorders, PTSD, and substance abuse/dependence disorders).
Subjects with BD can be classified into several trajectories of clinically relevant domains that are prognostically relevant and show differing degrees of associations with a broad range of negative clinical risk factors. The highest level of psychosocial disability was found in subjects with chronic mixed and depressive symptoms, who show limited improvement despite guideline-based treatment.
Inflammation and maternal or fetal infections have been suggested as risk factors for schizophrenia (SZ) and bipolar disorder (BP). It is likely that such environmental effects are contingent on ...genetic background. Here, in a genome-wide approach, we test the hypothesis that such exposures increase the risk for SZ and BP and that the increase is dependent on genetic variants. We use genome-wide genotype data, plasma IgG antibody measurements against Toxoplasma gondii, Herpes simplex virus type 1, Cytomegalovirus, Human Herpes Virus 6 and the food antigen gliadin as well as measurements of C-reactive protein (CRP), a peripheral marker of inflammation. The subjects are SZ cases, BP cases, parents of cases and screened controls. We look for higher levels of our immunity/infection variables and interactions between them and common genetic variation genome-wide. We find many of the antibody measurements higher in both disorders. While individual tests do not withstand correction for multiple comparisons, the number of nominally significant tests and the comparisons showing the expected direction are in significant excess (permutation p=0.019 and 0.004 respectively). We also find CRP levels highly elevated in SZ, BP and the mothers of BP cases, in agreement with existing literature, but possibly confounded by our inability to correct for smoking or body mass index. In our genome-wide interaction analysis no signal reached genome-wide significance, yet many plausible candidate genes emerged. In a hypothesis driven test, we found multiple interactions among SZ-associated SNPs in the HLA region on chromosome 6 and replicated an interaction between CMV infection and genotypes near the CTNNA3 gene reported by a recent GWAS. Our results support that inflammatory processes and infection may modify the risk for psychosis and suggest that the genotype at SZ-associated HLA loci modifies the effect of these variables on the risk to develop SZ.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This randomized, noninferiority trial compared ketamine with electroconvulsive therapy in treatment-resistant depression. Ketamine was noninferior to ECT for treatment-resistant depression without ...psychosis.
•Lithium declined by more than double to ~15% of visits for bipolar disorder in the US.•SGAs or mood stabilizing anticonvulsants increased to ~75%.•Polytherapy increased by ~3% every two ...years.•Antidepressants without other mood stabilizers decreased to ~7.5%.
Studies have shown that rates of lithium use for bipolar disorder in the United States declined through the 1990s as other mood stabilizing anticonvulsants and second-generation antipsychotics (SGAs) became more popular. We examined trends of medications for bipolar disorder from 1996 to 2015.
Twenty years of data from the National Ambulatory Medical Care Survey (NAMCS) were used. Weighted percentages of reported use of lithium, anticonvulsants, SGAs and antidepressants were calculated over two-year intervals. Logistic regression was used to examine factors related to polytherapy.
Reported use of lithium declined from 38.1% (95%CI: 29.8% - 46.3%) in 1996–97 to 14.3% (95%CI: 10.6% - 18.1%) in 2006–07 and has remained stable since. During this time, reports of SGAs more than doubled. SGAs and/or anticonvulsants were reported in 75.4% (95%CI: 69.5% - 81.3%) of visits with bipolar diagnoses in 2014–15. Polytherapy increased by approximately 3% every two years and in 2014–15 occurred in over 30% of visits. Antidepressants were reported in 40–50% of visits, but their reported use without other mood stabilizers decreased from 18.2% (95%CI: 11.7% - 24.8%) in 1998–99 to 7.5% (95%CI: 4.2% - 10.9%) in 2014–15.
The sample had limited power to study the effect of individual medications or the potential for differing effects in certain sub-groups of patients.
This study further documents the declining use of lithium for bipolar disorder, and corresponding increase in use of anticonvulsants and SGAs, despite the fact that lithium is typically recommended as a first line therapy for bipolar disorder.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Although accurate differentiation between bipolar disorder (BD) and unipolar major depressive disorder (MDD) has important prognostic and therapeutic implications, the distinction is often ...challenging based on clinical grounds alone. In this study, we tested whether psychiatric polygenic risk scores (PRSs) improve clinically based classification models of BD v. MDD diagnosis.
Our sample included 843 BD and 930 MDD subjects similarly genotyped and phenotyped using the same standardized interview. We performed multivariate modeling and receiver operating characteristic analysis, testing the incremental effect of PRSs on a baseline model with clinical symptoms and features known to associate with BD compared with MDD status.
We found a strong association between a BD diagnosis and PRSs drawn from BD (R2 = 3.5%, p = 4.94 × 10-12) and schizophrenia (R2 = 3.2%, p = 5.71 × 10-11) genome-wide association meta-analyses. Individuals with top decile BD PRS had a significantly increased risk for BD v. MDD compared with those in the lowest decile (odds ratio 3.39, confidence interval 2.19-5.25). PRSs discriminated BD v. MDD to a degree comparable with many individual symptoms and clinical features previously shown to associate with BD. When compared with the full composite model with all symptoms and clinical features PRSs provided modestly improved discriminatory ability (ΔC = 0.011, p = 6.48 × 10-4).
Our study demonstrates that psychiatric PRSs provide modest independent discrimination between BD and MDD cases, suggesting that PRSs could ultimately have utility in subjects at the extremes of the distribution and/or subjects for whom clinical symptoms are poorly measured or yet to manifest.
Item 9 of the Patient Health Questionnaire (PHQ) evaluates passive thoughts of death or self-injury within the last two weeks, and is often used to screen depressed patients for suicide risk. We ...aimed to validate the PHQ-9 item 9 with a brief electronic version of the Columbia Suicide Severity Rating Scale (eC-SSRS).
We analyzed data from 841 patients enrolled in the National Network of Depression Centers Clinical Care Registry. We performed a validation analysis of PHQ-9 item 9 for suicide risk and ideation, using the eC-SSRS as a gold standard (defined as positive response to suicidal ideation with intent to act or recent suicidal behavior).
Of the 841 patients, 13.4% and 41.1% were assessed as being positive for suicide risk by the eC-SSRS and PHQ-9 item 9, respectively. For the overall cohort, sensitivity was 87.6% (95%CI 80.2–92.5%), specificity was 66.1% (95%CI 62.6–69.4%), PPV was 28.6% (95%CI 24.1–33.6%), and NPV was 97.2% (95%CI 95.3–98.3%) for the PHQ-9 suicide item. These performance measures varied within subgroups defined by demographic and clinical characteristics. In addition, the validity of PHQ-9 item 9 (cutoff score of 1) with eC-SSRS-defined suicide ideation showed overall poor results.
The gold standard used in our study was a surrogate measure of suicidality based on eC-SSRS scores.
The results of our study suggest that item 9 of the PHQ-9 is an insufficient assessment tool for suicide risk and suicide ideation, with limited utility in certain demographic and clinical subgroups that requires further investigation.
•The PHQ-9 item 9 is an insufficient assessment tool for suicide risk and ideation.•The PHQ-9 item 9 has limited utility in certain subgroups.•The PHQ-9 item 9 should be used with a validated suicide risk inventory.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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