-
1.
Insight into susceptibility genes associated with bipolar disorder: a systematic review.
Kalcev, G, Preti, A, Scano, A, Orrù, G, Carta, MG
European review for medical and pharmacological sciences. 2021;(18):5701-5724
Abstract
OBJECTIVE Bipolar disorder (BD) is a severe disorder, and it is associated with an increased risk of mortality. About 25% of patients with BD have attempted and 11% have died by suicide. All these characteristics suggest that the disorders within the bipolar spectrum are a crucial public health problem. With the development of molecular genetics in recent decades, it was possible to more easily detect risk genes associated with this disorder. This study aimed at summarizing the findings of systematic reviews and meta-analyses on the topic and assessing the quality of the available evidence. MATERIALS AND METHODS PubMed/Medline and Web of Science were searched to identify systematic reviews and meta-analyses published during 2013-2019. Standard methodology was applied to synthesize and assess the retrieved literature. RESULTS This systematic review identifies a number of potential risk genes associated with bipolar disorder whose mechanism of action has yet to be confirmed. They are divided into several groups: 1) a list of the most significant susceptibility genetic factors associated with BD; 2) the implication of the ZNF804A gene in BD; 3) the role of genes involved in calcium signaling in BD; 4) DNA methylation in BD; 5) BD and risk suicide genes; 6) susceptibility genes for early-onset BD; 7) candidate genes common to both BD and schizophrenia; 8) genes involved in cognitive status in BD cases; 9) genes involved in structural alteration in BD brain tissue; 10) genes involved in lithium response in BD. CONCLUSIONS Future research should concentrate on molecular mechanisms by which genetic variants play a major role in BD. Supplemental research is needed to replicate the applicable results.
-
2.
Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.
Mullins, N, Forstner, AJ, O'Connell, KS, Coombes, B, Coleman, JRI, Qiao, Z, Als, TD, Bigdeli, TB, Børte, S, Bryois, J, et al
Nature genetics. 2021;(6):817-829
-
-
Free full text
-
Abstract
Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
-
3.
Serum folate levels in bipolar disorder: a systematic review and meta-analysis.
Hsieh, YC, Chou, LS, Lin, CH, Wu, HC, Li, DJ, Tseng, PT
BMC psychiatry. 2019;(1):305
Abstract
BACKGROUND Bipolar disorder (BD) is a major psychiatric illness, however its physiopathology is unclear. The role of folate in the physiopathology of BD is controversial. We conducted this systematic review and meta-analysis to investigate the effect of folate in BD patients. METHODS We performed a thorough literature study of the PubMed, Embase, ScienceDirect, ClinicalKey, Cochrane Library, ProQuest, Web of Science, and ClinicalTrials.gov databases until December 21st, 2018. Random effects meta-analysis was conducted. RESULTS Six articles involving 481 patients with BD and 760 controls were included. The meta-analysis results suggested that serum folate levels in the patients with BD were significantly lower than those in the controls (Hedges' g = - 0.211, 95% confidence interval = - 0.391 to - 0.031, p = 0.021). CONCLUSION The current meta-analysis show it might be association between lower serum folate levels and patient with BD. However, we could not distinguish the potentially confounding effects of mood states on the folate levels. Further prospective studies including subjects with different mood states and possible physiopathology are warranted to investigate the association between folate deficiency and the etiology of BD.
-
4.
N-acetylcysteine for major mental disorders: a systematic review and meta-analysis of randomized controlled trials.
Zheng, W, Zhang, QE, Cai, DB, Yang, XH, Qiu, Y, Ungvari, GS, Ng, CH, Berk, M, Ning, YP, Xiang, YT
Acta psychiatrica Scandinavica. 2018;(5):391-400
Abstract
OBJECTIVE This systematic review and meta-analysis of randomized controlled trials (RCTs) examined the efficacy and safety of adjunctive N-acetylcysteine (NAC), an antioxidant drug, in treating major depressive disorder (MDD), bipolar disorder, and schizophrenia. METHODS The PubMed, Cochrane Library, PsycINFO, CNKI, CBM, and WanFang databases were independently searched and screened by two researchers. Standardized mean differences (SMDs), risk ratios, and their 95% confidence intervals (CIs) were computed. RESULTS Six RCTs (n = 701) of NAC for schizophrenia (three RCTs, n = 307), bipolar disorder (two RCTs, n = 125), and MDD (one RCT, n = 269) were identified and analyzed as separate groups. Adjunctive NAC significantly improved total psychopathology (SMD = -0.74, 95% CI: -1.43, -0.06; I2 = 84%, P = 0.03) in schizophrenia, but it had no significant effect on depressive and manic symptoms as assessed by the Young Mania Rating Scale in bipolar disorder and only a small effect on major depressive symptoms. Adverse drug reactions to NAC and discontinuation rates between the NAC and control groups were similar across the three disorders. CONCLUSIONS Adjunctive NAC appears to be a safe treatment that has efficacy for schizophrenia, but not for bipolar disorder or MDD. Further higher quality RCTs are warranted to determine the role of adjunctive NAC in the treatment of major psychiatric disorders.
-
5.
Biological rationale and potential clinical use of gabapentin and pregabalin in bipolar disorder, insomnia and anxiety: protocol for a systematic review and meta-analysis.
Houghton, KT, Forrest, A, Awad, A, Atkinson, LZ, Stockton, S, Harrison, PJ, Geddes, JR, Cipriani, A
BMJ open. 2017;(3):e013433
Abstract
INTRODUCTION Gabapentin has been extensively prescribed off-label for psychiatric indications, with little established evidence of efficacy. Gabapentin and pregabalin, a very similar drug with the same mechanism of action, bind to a subunit of voltage-dependent calcium channels which are implicated in the aetiopathogenesis of bipolar disorder, anxiety and insomnia. This systematic review and meta-analysis aims to collect and critically appraise all the available evidence about the efficacy and tolerability of gabapentin and pregabalin in the treatment of bipolar disorder, insomnia and anxiety. METHODS AND ANALYSIS We will include all randomised controlled trials (RCTs) reported as double-blind and comparing gabapentin or pregabalin with placebo or any other active pharmacological treatment (any preparation, dose, frequency, route of delivery or setting) in patients with bipolar disorder, anxiety or insomnia. For consideration of adverse effects (tolerability), single-blind or open-label RCTs and non-randomised evidence will also be summarised. The main outcomes will be efficacy (measured as dichotomous and continuous outcome) and acceptability (proportion of patients who dropped out of the allocated treatment). Published and unpublished studies will be sought through relevant database searches, trial registries and websites; all reference selection and data extraction will be conducted by at least 2 independent reviewers. We will conduct a random-effects meta-analysis to synthesise all evidence for each outcome. Heterogeneity between studies will be investigated by the I2 statistic. Data from included studies will be entered into a funnel plot for investigation of small-study effects. No subgroup analysis will be undertaken, but we will carry out sensitivity analyses about combination treatment, psychiatric comorbidity, use of rescue medications and fixed versus random-effects model. ETHICS AND DISSEMINATION This review does not require ethical approval. This protocol has been registered on PROSPERO (CRD42016041802). The results of the systematic review will be disseminated via publication in a peer-reviewed journal.
-
6.
Does stress play a significant role in bipolar disorder? A meta-analysis.
Lex, C, Bäzner, E, Meyer, TD
Journal of affective disorders. 2017;:298-308
Abstract
BACKGROUND There is evidence that stressful life events (LE) play a crucial role in the etiology of bipolar affective disorder (BD). However, primary studies, as well as narrative reviews, have provided mixed results. The present meta-analysis combined and analyzed previous data in order to address these inconsistencies. METHOD Forty-two studies published in 53 records were identified by systematically searching MEDLINE, PsychINFO, and PSYCHINDEX using the terms "bipolar disorder" OR "manic-depressive" OR "bipolar affective disorder" OR "mania" AND "stress" OR "life event" OR "daily hassles" OR "goal attainment". Then, meta-analyses were conducted. RESULTS Individuals diagnosed with BD reported more LE before relapse when compared to euthymic phases. They also experienced more LE relative to healthy individuals and to physically ill patients. No significant difference in the number of LE was found when BD was compared to unipolar depression and schizophrenia. LIMITATIONS When interpreting the present meta-analytic findings one should keep in mind that most included studies were retrospective and often did not specify relevant information, e.g., if the LE were chronic or acute or if the individuals were diagnosed with BD I or II. We could not entirely rule out a publication bias. CONCLUSION The present meta-analyses found that individuals with BD were sensitive to LE, which corroborates recent theoretical models and psychosocial treatment approaches of BD. Childbirth, as a specific LE, affected individuals with BD more than individuals with unipolar depression. Future studies that investigate specific LE are warranted.
-
7.
Lamotrigine compared to placebo and other agents with antidepressant activity in patients with unipolar and bipolar depression: a comprehensive meta-analysis of efficacy and safety outcomes in short-term trials.
Solmi, M, Veronese, N, Zaninotto, L, van der Loos, ML, Gao, K, Schaffer, A, Reis, C, Normann, C, Anghelescu, IG, Correll, CU
CNS spectrums. 2016;(5):403-418
Abstract
OBJECTIVES To meta-analytically summarize lamotrigine's effectiveness and safety in unipolar and bipolar depression. METHODS We conducted systematic PubMed and SCOPUS reviews (last search =10/01/2015) of randomized controlled trials comparing lamotrigine to placebo or other agents with antidepressant activity in unipolar or bipolar depression. We performed a random-effects meta-analysis of depression ratings, response, remission, and adverse effects calculating standardized mean difference (SMD) and risk ratio (RR) ±95% confidence intervals (CIs). RESULTS Eighteen studies (n=2152, duration=9.83 weeks) in patients with unipolar depression (studies=4, n=187; monotherapy vs lithium=1, augmentation of antidepressants vs placebo=3) or bipolar depression (studies=14, n=1965; monotherapy vs placebo=5, monotherapy vs lithium or olanzapine+fluoxetine=2, augmentation of antidepressants vs placebo=1, augmentation of mood stabilizers vs placebo=3, augmentation of mood stabilizers vs trancylpromine, citalopram, or inositol=3) were meta-analyzed. Lamotrigine's efficacy for depressive symptoms did not differ significantly in monotherapy vs augmentation studies (vs. placebo: p=0.98, I2=0%; vs active agents: p=0.48, I2=0%) or in unipolar vs bipolar patients (vs placebo: p=0.60, I2=0%), allowing pooling of each placebo-controlled and active-controlled trials. Lamotrigine outperformed placebo regarding depressive symptoms (studies=11, n=713 vs n=696; SMD=-0.15, 95% CI=-0.27, -0.02, p=0.02, heterogeneity: p=0.24) and response (after removing one extreme outlier; RR=1.42, 95% CI=1.13-1.78; p=0.003, heterogeneity: p=0.08). Conversely, lamotrigine did not differ regarding efficacy on depressive symptoms, response, or remission from lithium, olanzapine+fluoxetine, citalopram, or inositol (studies=6, n=306 vs n=318, p-values=0.85-0.92). Adverse effects and all-cause/specific-cause discontinuation were similar across all comparisons. CONCLUSIONS Lamotrigine was superior to placebo in improving unipolar and bipolar depressive symptoms, without causing more frequent adverse effects/discontinuations. Lamotrigine did not differ from lithium, olanzapine+fluoxetine, citalopram, or inositol.
-
8.
Physical activity and sedentary behavior in people with bipolar disorder: A systematic review and meta-analysis.
Vancampfort, D, Firth, J, Schuch, F, Rosenbaum, S, De Hert, M, Mugisha, J, Probst, M, Stubbs, B
Journal of affective disorders. 2016;:145-52
Abstract
BACKGROUND Mortality rates are approximately two to three times higher in people with bipolar disorder (BD) than in general population. Lack of physical activity (PA) and sedentary behavior (SB) are independent risk factors for cardiovascular disease and premature mortality. AIMS We conducted a meta-analysis to investigate PA and SB levels and its predictors in BD. METHODS Major electronic databases were searched from inception till 02/2016 for articles measuring PA and SB with a self-report questionnaire (SRQ) or objective measure (e.g. accelerometer) in BD. A random effects meta-analysis and meta-regression analysis were conducted. RESULTS Six studies were eligible including 279 (129♂) people with BD (mean age=43.9 years; range: 32.0-51.5 years). The trim and fill analysis demonstrated people with BD spent in total 210.1min (95%CI=146.3-273.9min) per day being physically active and 613.3min (95%CI=389.9-836.6min) during waking hours being sedentary. No significant difference in total PA per day was observed between people with BD and controls (g=-0.62, 95% CI=-1.55 to 0.31, I(2)=88.5%, n BD =82, n controls =86). Objective measures of PA recorded significantly lower levels (P=0.03) compared to self-report PA. Meta-regression demonstrated that older age and a higher body mass index predicted lower PA levels. LIMITATIONS Only a limited number of studies were identified assessing SB in people with BD. CONCLUSIONS Adults with BD engage in high levels of sedentary behavior during waking hours. Given that sedentary behavior is an independent predictor of cardiovascular disease, future lifestyle interventions specifically targeting the prevention of sedentary behavior are warranted.
-
9.
ZNF804A Genetic Variation Confers Risk to Bipolar Disorder.
Zhang, C, Wang, Z, Hong, W, Wu, Z, Peng, D, Fang, Y
Molecular neurobiology. 2016;(5):2936-2943
Abstract
Genetic variation in the gene encoding zinc finger protein 804A gene (ZNF804A) has been identified to be associated with bipolar disorder in genome-wide association studies, while little is known regarding their association in Asian populations. In this study, we aimed to examine whether ZNF804A may confer susceptibility to BD in Han Chinese. We measured the mRNA expression level of ZNF804A in patients with BD and controls. Two functional variants (rs1344706 and rs359895) in ZNF804A were genotyped among 1508 individuals with or without BD. We then performed a meta-analysis based on present literature. Our results showed that ZNF804A mRNA level in peripheral blood mononuclear cells was significantly higher in BD patients than that in controls (P = 0.01). The rs1344706 showed significant allelic association with BD (P = 0.034). The frequency of T allele of rs1344706 was higher in patients than that in controls (odds ratio = 1.19, 95 % confidence interval 1.03-1.37). After pooling all data, meta-analysis indicated a significant association of rs1344706 with BD (P = 0.0003). Furthermore, we performed an eQTL analysis and observed significant associations between rs1344706 and ZNF804A expression level in hippocampus (P = 0.032) and occipital cortex (P = 0.036). After stratified by diagnosis, the association of rs1344706 with BD was only survived in BD-I (genotypic P = 0.04, allelic P = 0.014), but not in BD-II. Our findings provided supportive evidence for the involvement of ZNF804A rs1344706 in BD, especially in BD-I.
-
10.
Leptin in bipolar disorder: A systematic review and meta-analysis.
Fernandes, BS, Dash, S, Jacka, F, Dodd, S, Carvalho, AF, Köhler, CA, Steiner, J, da Graça Cantarelli, M, Nardin, P, Gonçalves, CA, et al
European psychiatry : the journal of the Association of European Psychiatrists. 2016;:1-7
Abstract
BACKGROUND Bipolar disorder (BD) is a psychiatric disorder associated with increased rates of obesity and inflammation. Leptin is an adipokine that is mainly produced by the white adipose tissue in response to insulin. It stimulates the immune system, increasing the production of pro-inflammatory cytokines. There is currently uncertainty regarding possible alterations in peripheral leptin levels across the mood states in BD. METHODS This study comprises a between-group meta-analysis comparing serum and plasma leptin levels in people with BD in mania, depression or euthymia and healthy controls. We conducted a systematic search for all possibly eligible-English and non-English peer-reviewed articles. We calculated the effect size (ES) utilizing Hedges' adjusted g using random effects. RESULTS Eleven studies were included in the meta-analyses, providing data on 1118 participants. Serum and plasma leptin levels were not altered in subjects with BD when compared to healthy controls in mania (g=-0.99, 95% CI -2.43 to 0.43, P=0.171), in depression (g=0.17, 95% CI -0.45 to 0.79, P=0.584), or in euthymia (g=0.03, 95% CI -0.39 to 0.46, P=0.882). However, we did observe a stronger association between leptin levels and both age and BMI in patients with BD in euthymia compared to healthy controls, such that the greater the age of the individuals, the greater the difference in leptin levels between BD and controls; and the higher the BMI, the greater the difference in leptin levels between BD and controls. CONCLUSIONS Our meta-analysis provides evidence that leptin levels are not altered in BD across the mood spectrum compared to healthy controls. The disproportionate increase of leptin levels with increase in BMI in BD speaks in favour of a potential inflammatory role of white adipose tissue in BD and a disproportionate increase of leptin levels with increase in age.