Lithium Prescribing during Pregnancy: A UK Primary Care Database Study

Women taking lithium must decide whether to continue the medication if they conceive or plan to conceive. Little is known about the extent of prescribing of lithium during pregnancy

Bereavement by suicide as a risk factor for suicide attempt: a cross-sectional national UK-wide study of 3432 young bereaved adults

OBJECTIVES: US and UK suicide prevention strategies suggest that bereavement by the suicide of a relative or friend is a risk factor for suicide. However, evidence is lacking that the risk exceeds that of any sudden bereavement, is specific to suicide, or applies to peer suicide. We conducted the first controlled UK-wide study to test the hypothesis that young adults bereaved by suicide have an increased risk of suicidal ideation and suicide attempt compared with young adults bereaved by other sudden deaths. DESIGN: National cross-sectional study. SETTING: Staff and students at 37 UK higher educational institutions in 2010. PARTICIPANTS: 3432 eligible respondents aged 18-40 exposed to sudden bereavement of a friend or relative after the age of 10. EXPOSURES: Bereavement by suicide (n=614), by sudden unnatural causes (n=712) and by sudden natural causes (n=2106). PRIMARY OUTCOME MEASURES: Incident suicidal ideation and suicide attempt. FINDINGS: Adults bereaved by suicide had a higher probability of attempting suicide (adjusted OR (AOR)=1.65; 95% CI 1.12 to 2.42; p=0.012) than those bereaved by sudden natural causes. There was no such increased risk in adults bereaved by sudden unnatural causes. There were no group differences in probability of suicidal ideation. The effect of suicide bereavement was similar whether bereaved participants were blood-related to the deceased or not. The significant association between bereavement by suicide and suicide attempt became non-significant when adding perceived stigma (AOR=1.11; 95% CI 0.74 to 1.67; p=0.610). When compared with adults bereaved by sudden unnatural causes, those bereaved by suicide did not show significant differences in suicide attempt (AOR=1.48; 95% CI 0.94 to 2.33; p=0.089). CONCLUSIONS: Bereavement by suicide is a specific risk factor for suicide attempt among young bereaved adults, whether related to the deceased or not. Suicide risk assessment of young adults should involve screening for a history of suicide in blood relatives, non-blood relatives and friends

Individual and area-level risk factors for suicidal ideation and attempt in people with severe depression

INTRODUCTION: Previous research has identified several risk factors that are strongly associated with suicidal behavior in patients with severe depression. However, the effects of area-level characteristics on suicidal ideation and attempt in this population remain unclear. METHODS: The Clinical Record Interactive Search (CRIS) database was used to identify 2587 patients with severe depression who received secondary mental health services from the Camden & Islington NHS Foundation Trust. Stepwise multivariable logistic regression models were used to examine associations between socio-demographic characteristics, clinical variables, area-level measures, and suicidal ideation and attempt as separate outcomes. RESULTS: Both suicidal ideation and attempts were common among this cohort of severely depressed individuals (70.5% and 37.7%, respectively). While several individual socio-demographic and clinical characteristics were associated with both outcomes, particularly past psychiatric admission (suicidal ideation: adjusted OR=2.86, 95% CI: 2.26-3.62; suicide attempt: adjusted OR=4.00, 95% CI: 3.30-4.89), neither social deprivation nor ethnic density (measured at the area-level) was associated with risk for either outcome. LIMITATIONS: Data were not collected specifically for research purposes and hence information on some potential confounders was not available. Additionally, information was restricted to individuals who accessed secondary mental health services in a defined catchment area and period. The study therefore does not take into account individuals who did not access mental health services. CONCLUSIONS: The variation in risk for suicidal ideation and attempt among severely depressed individuals is explained by differences in individual socio-demographic and clinical characteristics, most notably past psychiatric admission and substance misuse, and not by area-level measures

A CRISPR/Cas9-generated mutation in the zebrafish orthologue of PPP2R3B causes idiopathic scoliosis

Idiopathic scoliosis (IS) is the deformation and/or abnormal curvature of the spine that develops progressively after birth. It is a very common condition, affecting approximately 4% of the general population, yet the genetic and mechanistic causes of IS are poorly understood. Here, we focus on PPP2R3B, which encodes a protein phosphatase 2A regulatory subunit. We found that PPP2R3B is expressed at sites of chondrogenesis within human foetuses, including the vertebrae. We also demonstrated prominent expression in myotome and muscle fibres in human foetuses, and zebrafish embryos and adolescents. As there is no rodent orthologue of PPP2R3B, we used CRIPSR/Cas9-mediated gene-editing to generate a series of frameshift mutations in zebrafish ppp2r3b. Adolescent zebrafish that were homozygous for this mutation exhibited a fully penetrant kyphoscoliosis phenotype which became progressively worse over time, mirroring IS in humans. These defects were associated with reduced mineralisation of vertebrae, resembling osteoporosis. Electron microscopy demonstrated abnormal mitochondria adjacent to muscle fibres. In summary, we report a novel zebrafish model of IS and reduced bone mineral density. In future, it will be necessary to delineate the aetiology of these defects in relation to bone, muscle, neuronal and ependymal cilia function

Self-harm, Unintentional Injury, and Suicide in Bipolar Disorder During Maintenance Mood Stabilizer Treatment: A UK Population-Based Electronic Health Records Study

Importance: Self-harm is a prominent cause of morbidity in patients with bipolar disorder and is strongly associated with suicide. There is evolving evidence that lithium use may reduce suicidal behavior, in addition to concerns that the use of anticonvulsants may increase self-harm. Information is limited about the effects of antipsychotics when used as mood stabilizer treatment. Rates of unintentional injury are poorly defined in bipolar disorder, and understanding drug associations with this outcome may shed light on mechanisms for lithium's potential antisuicidal properties through reduction in impulsive aggression. Objective: To compare rates of self-harm, unintentional injury, and suicide in patients with bipolar disorder who were prescribed lithium, valproate sodium, olanzapine, or quetiapine fumarate. Design, Setting, and Participants: This investigation was a propensity score (PS)-adjusted and PS-matched longitudinal cohort study in a nationally representative UK sample using electronic health records data collected between January 1, 1995, and December 31, 2013. Participants included all patients diagnosed as having bipolar disorder who were prescribed lithium, valproate, olanzapine, or quetiapine as maintenance mood stabilizer treatment. Main Outcomes and Measures: The primary outcome was any form of self-harm. Secondary outcomes were unintentional injury and suicide. Results: Of the 14 396 individuals with a diagnosis of BPD, 6671 were included in the cohort, with 2148 prescribed lithium, 1670 prescribed valproate, 1477 prescribed olanzapine, and 1376 prescribed quetiapine as maintenance mood stabilizer treatment. Self-harm rates were lower in patients prescribed lithium (205; 95% CI, 175-241 per 10 000 person-years at risk [PYAR]) compared with those prescribed valproate (392; 95% CI, 334-460 per 10 000 PYAR), olanzapine (409; 95% CI, 345-483 per 10 000 PYAR), or quetiapine (582; 95% CI, 489-692 per 10 000 PYAR). This association was maintained after PS adjustment (hazard ratio [HR], 1.40; 95% CI, 1.12-1.74 for valproate, olanzapine, or quetiapine vs lithium) and PS matching (HR, 1.51; 95% CI, 1.21-1.88). After PS adjustment, unintentional injury rates were lower for lithium compared with valproate (HR, 1.32; 95% CI, 1.10-1.58) and quetiapine (HR, 1.34; 95% CI, 1.07-1.69) but not olanzapine. The suicide rate in the cohort was 14 (95% CI, 9-21) per 10 000 PYAR. Although this rate was lower in the lithium group than for other treatments, there were too few events to allow accurate estimates. Conclusions and Relevance: Patients taking lithium had reduced self-harm and unintentional injury rates. This finding augments limited trial and smaller observational study results. It supports the hypothesis that lithium use reduces impulsive aggression in addition to stabilizing mood

Antiepileptic drugs prescribed in pregnancy and prevalence of major congenital malformations: comparative prevalence studies.

OBJECTIVE: The aim of this study was to examine the prevalence of major congenital malformations associated with antiepileptic drug (AED) treatment in pregnancy. PATIENTS AND METHODS: Using data from The Health Improvement Network, we identified women who have given live birth and their offspring. Four subgroups were selected based on the AED treatment in early pregnancy, valproate, carbamazepine, lamotrigine and women not receiving AED treatment. We compared the prevalence of major congenital malformations within children of these four groups and estimated prevalence ratios (PRs) using Poisson regression adjusted for maternal age, sex of child, quintiles of Townsend deprivation score and indication for treatment. RESULTS: In total, 240,071 women were included in the study. A total of 229 women were prescribed valproate in pregnancy, 357 were prescribed lamotrigine and 334 were prescribed carbamazepine and 239,151 women were not prescribed AEDs. Fifteen out of 229 (6.6%) women prescribed valproate gave birth to a child with a major congenital malformation. The figures for lamotrigine, carbamazepine and women not prescribed AEDs were 2.7%, 3.3% and 2.2%, respectively. The prevalence of major congenital malformation was similar for women prescribed lamotrigine or carbamazepine compared to women with no AED treatment in pregnancy. For women prescribed valproate in polytherapy, the prevalence was fourfold higher. After adjustments, the effect of estimates attenuated, but the prevalence remained two- to threefold higher in women prescribed valproate. CONCLUSION: The results of our study suggest that lamotrigine and carbamazepine are safer treatment options than valproate in pregnancy and should be considered as alternative treatment options for women of childbearing potential and in pregnancy

Prescribing of antipsychotics in UK primary care: a cohort study.

To examine the recorded indication for antipsychotic prescriptions in UK primary care

A CRISPR/Cas9-generated mutation in the zebrafish orthologue of PPP2R3B causes idiopathic scoliosis.

Idiopathic scoliosis (IS) is the deformation and/or abnormal curvature of the spine that develops progressively after birth. It is a very common condition, affecting approximately 4% of the general population, yet the genetic and mechanistic causes of IS are poorly understood. Here, we focus on PPP2R3B, which encodes a protein phosphatase 2A regulatory subunit. We found that PPP2R3B is expressed at sites of chondrogenesis within human foetuses, including the vertebrae. We also demonstrated prominent expression in myotome and muscle fibres in human foetuses, and zebrafish embryos and adolescents. As there is no rodent orthologue of PPP2R3B, we used CRIPSR/Cas9-mediated gene-editing to generate a series of frameshift mutations in zebrafish ppp2r3b. Adolescent zebrafish that were homozygous for this mutation exhibited a fully penetrant kyphoscoliosis phenotype which became progressively worse over time, mirroring IS in humans. These defects were associated with reduced mineralisation of vertebrae, resembling osteoporosis. Electron microscopy demonstrated abnormal mitochondria adjacent to muscle fibres. In summary, we report a novel zebrafish model of IS and reduced bone mineral density. In future, it will be necessary to delineate the aetiology of these defects in relation to bone, muscle, neuronal and ependymal cilia function

A systematic review and meta-analysis of premature mortality in bipolar affective disorder

Objective To review and complete meta-analysis of studies estimating standardised mortality ratios (SMRs) in bipolar affective disorder (BPAD) for all-cause and cause-specific mortalities. Method Cause-specific mortality was grouped into natural and unnatural causes. These subgroups were further divided into circulatory, respiratory, neoplastic and infectious causes, and suicide and other violent deaths. Summary SMRs were calculated using random-effects meta-analysis. Heterogeneity was examined via subgroup analysis and meta-regression. Results Systematic searching found 31 studies meeting inclusion criteria. Summary SMR for all-cause mortality = 2.05 (95% CI 1.89–2.23), but heterogeneity was high (I2 = 96.2%). This heterogeneity could not be accounted for by date of publication, cohort size, mid-decade of data collection, population type or geographical region. Unnatural death summary SMR = 7.42 (95% CI 6.43–8.55) and natural death = 1.64 (95% CI 1.47–1.83). Specifically, suicide SMR = 14.44 (95% CI 12.43–16.78), other violent death SMR = 3.68 (95% CI 2.77–4.90), deaths from circulatory disease = 1.73 (95% CI 1.54–1.94), respiratory disease = 2.92 (95% CI 2.00–4.23), infection = 2.25 (95% CI 1.70–3.00) and neoplasm = 1.14 (95% CI 1.10–1.21). Conclusion Despite considerable heterogeneity, all summary SMR estimates and a large majority of individual studies showed elevated mortality in BPAD compared to the general population. This was true for all causes of mortality studied