Joseph Hayes

Prescribing trends in bipolar disorder: cohort study in the United Kingdom THIN primary care database 1995-2009.

Objectives To determine changes in prescribing patterns in primary care of antipsychotic and mood stabiliser medication in a representative sample of patients with bipolar disorder in the United Kingdom over a fifteen year period and association with socio-demographic factors. Methods We identified 4700 patients in the Health Improvement Network (THIN) primary care database, who had received treatment for bipolar disorder between 1995 and 2009. The proportion of time for which each individual was prescribed a particular medication was studied, along with variation by sex, age and social depravation status (quintiles of Townsend scores). The number of drugs an individual was taking within a particular year was also examined. Results In 1995, 40.6% of patients with bipolar disorder were prescribed a psychotropic medication at least twice. By 2009 this had increased to 78.5% of patients. Valproate registered with the greatest increase in use (22.7%) followed by olanzapine (15.7%) and quetiapine (9.9%). There were differences by age and sex; with young (18–30 year old) women having the biggest increase in proportion of time on medication. There were no differences by social deprivation status. By 2009, 34.2% of women of childbearing age were treated with valproate. Conclusions Lithium use overall remained relatively constant, whilst second generation antipsychotic and valproate use increased dramatically. Changes in prescribing practice preceded published trial evidence, especially with the use of second generation antipsychotics, perhaps with inferences being made from treatment of schizophrenia and use of first generation antipsychotics. Women of childbearing age were prescribed valproate frequently, against best advice.

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

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.

Recording of Severe Mental Illness in United Kingdom Primary Care, 2000–2010

Background There is increasing emphasis on primary care services for individuals with severe mental illnesses (SMI), including schizophrenia, bipolar disorder, and other non-organic psychotic disorders. However we lack information on how many people receive these different diagnoses in primary care. Primary care databases offer an opportunity to explore the recording of new SMI diagnoses in representative general practices. Methods We used data from The UK Health Improvement Network (THIN) primary care database including longitudinal patient records for individuals aged over 16 years from 437 general practices. We determined the annual GP recorded rate of first diagnosis of SMI by age, gender, social deprivation and urbanicity between 2000 and 2010. Results We identified 10,520 individuals with a first record of schizophrenia, bipolar disorder or other non-organic psychosis among 4,164,794 patients. This corresponded to a rate of first diagnosis of 46.4 per 100,000 person years at risk (PYAR) (95% CI 45.4 to 47.4) in the 16–65 age group. The rate of first record of schizophrenia was 9.2 per 100,000 PYAR (95% CI 8.7 to 9.6) in this age group, bipolar disorder was 15.0 per 100,000 PYAR (95% CI 14.4 to 15.5) and other non-organic psychotic disorder was 22.3 per 100,000 PYAR (95% CI 21.6 to 23.0). Conclusions The rates of GP recorded SMI in primary care records were broadly comparable to incidence rates from previous epidemiological studies of SMI and show similar patterns by socio-demographic characteristics. However there were some differences by specific diagnoses. GPs may be recording rates that are higher than those used to commission services.

Mortality gap for people with bipolar disorder and schizophrenia: UK-based cohort study 2000–2014

Background Bipolar disorder and schizophrenia are associated with increased mortality relative to the general population. There is an international emphasis on decreasing this excess mortality. Aims To determine whether the mortality gap between individuals with bipolar disorder and schizophrenia and the general population has decreased. Method A nationally representative cohort study using primary care electronic health records from 2000 to 2014, comparing all patients diagnosed with bipolar disorder or schizophrenia and the general population. The primary outcome was all-cause mortality. Results Individuals with bipolar disorder and schizophrenia had elevated mortality (adjusted hazard ratio (HR) = 1.79, 95% CI 1.67–1.88 and 2.08, 95% CI 1.98–2.19 respectively). Adjusted HRs for bipolar disorder increased by 0.14/year (95% CI 0.10–0.19) from 2006 to 2014. The adjusted HRs for schizophrenia increased gradually from 2004 to 2010 (0.11/year, 95% CI 0.04–0.17) and rapidly after 2010 (0.34/year, 95% CI 0.18–0.49). Conclusions The mortality gap between individuals with bipolar disorder and schizophrenia, and the general population is widening.

Lithium vs. valproate vs. olanzapine vs. quetiapine as maintenance monotherapy for bipolar disorder: a population‐based UK cohort study using electronic health records

It is unclear which maintenance treatment for bipolar disorder is superior in clinical practice. Randomized controlled head‐to‐head trials of available drugs either do not exist or are inconclusive. We aimed to compare rates of monotherapy treatment failure in individuals prescribed lithium, valproate, olanzapine or quetiapine by a population‐based cohort study using electronic health records. 5,089 patients with bipolar disorder were prescribed lithium (N=1,505), valproate (N=1,173) olanzapine (N=1,366) or quetiapine (N=1,075) as monotherapy. Treatment failure was defined as time to stopping medication or add‐on of another mood stabilizer, antipsychotic, antidepressant or benzodiazepine. In unadjusted analyses, the duration of successful monotherapy was longest in individuals treated with lithium. Treatment failure had occurred in 75% of those prescribed lithium by 2.05 years (95% CI: 1.63‐2.51), compared to 0.76 years (95% CI: 0.64‐0.84) for those prescribed quetiapine, 0.98 years (95% CI: 0.84‐1.18) for those prescribed valproate, and 1.13 years for those prescribed olanzapine (95% CI: 1.00‐1.31). Lithiums superiority remained in a propensity score matched analysis; when treatment failure was defined as stopping medication or add‐on of a mood stabilizer or antipsychotic; and when treatment failure was restricted to more than three months after commencing the study drug. Lithium appears to be more successful as monotherapy maintenance treatment than valproate, olanzapine or quetiapine. Lithium is often avoided because of its side effect profile, but alternative treatments may reduce the time to being prescribed more than one drug, with potential additive side effects of these treatments.

Adverse renal, endocrine, hepatic and metabolic events during maintenance mood stabilizer treatment for bipolar disorder: a population based cohort study

Background There is limited, poorly characterized information about adverse events occurring during maintenance treatment of bipolar disorder. We aimed to determine adverse event rates during treatment with lithium, valproate, olanzapine, and quetiapine. Methods and Findings We conducted a propensity score adjusted cohort study using nationally representative United Kingdom electronic health records from January 1, 1995, until December 31, 2013. We included patients who had a diagnosis of bipolar disorder and were prescribed lithium (n = 2148), valproate (n = 1670), olanzapine (n = 1477), or quetiapine (n = 1376) as maintenance mood stabilizer treatment. Adverse outcomes were chronic kidney disease, thyroid disease, hypercalcemia, weight gain, hypertension, type 2 diabetes mellitus, cardiovascular disease, and hepatotoxicity. The propensity score included important demographic, physical health, and mental health predictors of drug treatment allocation. The median duration of drug treatment was 1.48 y (interquartile range 0.64–3.43). Compared to patients prescribed lithium, those taking valproate, olanzapine, and quetiapine had reduced rates of chronic kidney disease stage 3 or more severe, following adjustment for propensity score, age, and calendar year, and accounting for clustering by primary care practice (valproate hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.45–0.69; p < 0.001, olanzapine HR 0.57; 95% CI 0.45–0.71; p < 0.001, quetiapine HR 0.62; 95% CI 0.47–0.80; p < 0.001). Hypothyroidism was reduced in those taking valproate (HR 0.60; 95% CI 0.40–0.89; p = 0.012) and olanzapine (HR 0.48; 95% CI 0.29–0.77; p = 0.003), compared to those taking lithium. Rates of new onset hyperthyroidism (valproate HR 0.24; 95% CI 0.09–0.61; p = 0.003, olanzapine HR 0.31; 95% CI 0.13–0.73; p = 0.007) and hypercalcemia (valproate HR 0.25; 95% CI 0.10–0.60; p = 0.002, olanzapine HR 0.32; 95% CI 0.14–0.76; p = 0.008, quetiapine HR 0.23; 95% CI 0.07–0.73; p = 0.013) were also reduced relative to lithium. However, rates of greater than 15% weight gain on valproate, olanzapine, and quetiapine were higher (valproate HR 1.62; 95% CI 1.31–2.01; p < 0.001, olanzapine HR 1.84; 95% CI 1.47–2.30; p < 0.001, quetiapine HR 1.67; 95% CI 1.24–2.20; p < 0.001) than in individuals prescribed lithium, as were rates of hypertension in the olanzapine treated group (HR 1.41, 95% CI 1.06–1.87; p = 0.017). We found no significant difference in rates of chronic kidney disease stage 4 or more severe, type 2 diabetes mellitus, cardiovascular disease, or hepatotoxicity. Despite estimates being robust following sensitivity analyses, limitations include the potential for residual confounding and ascertainment bias and an inability to examine dosage effects. Conclusions Lithium use is associated with more renal and endocrine adverse events but less weight gain than commonly used alternative mood stabilizers. Risks need to be offset with the effectiveness and anti-suicidal benefits of lithium and the potential metabolic side effects of alternative treatment options.

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 lithiums 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.

Interconnected or disconnected? Promotion of mental health and prevention of mental disorder in the digital age

To date there have been few peer-reviewed studies on the feasibility, acceptability and effectiveness of digital technologies for mental health promotion and disorder prevention. Any evaluation of these evolving technologies is complicated by a lack of understanding about the specific risks and possible benefits of the many forms of internet use on mental health. To adequately meet the mental health needs of todays society, psychiatry must engage in rigorous assessment of the impact of digital technologies.

The effect of sibutramine prescribing in routine clinical practice on cardiovascular outcomes: a cohort study in the United Kingdom.

Background/Objectives:The marketing authorization for the weight loss drug sibutramine was suspended in 2010 following a major trial that showed increased rates of non-fatal myocardial infarction and cerebrovascular events in patients with pre-existing cardiovascular disease. In routine clinical practice, sibutramine was already contraindicated in patients with cardiovascular disease and so the relevance of these influential clinical trial findings to the ‘real World’ population of patients receiving or eligible for the drug is questionable. We assessed rates of myocardial infarction and cerebrovascular events in a cohort of patients prescribed sibutramine or orlistat in the United Kingdom.Subjects/Methods:A cohort of patients prescribed weight loss medication was identified within the Clinical Practice Research Datalink. Rates of myocardial infarction or cerebrovascular event, and all-cause mortality were compared between patients prescribed sibutramine and similar patients prescribed orlistat, using both a multivariable Cox proportional hazard model, and propensity score-adjusted model. Possible effect modification by pre-existing cardiovascular disease and cardiovascular risk factors was assessed.Results:Patients prescribed sibutramine (N=23 927) appeared to have an elevated rate of myocardial infarction or cerebrovascular events compared with those taking orlistat (N=77 047; hazard ratio 1.69, 95% confidence interval 1.12–2.56). However, subgroup analysis showed the elevated rate was larger in those with pre-existing cardiovascular disease (hazard ratio 4.37, 95% confidence interval 2.21–8.64), compared with those with no cardiovascular disease (hazard ratio 1.52, 95% confidence interval 0.92–2.48, P-interaction=0.0076). All-cause mortality was not increased in those prescribed sibutramine (hazard ratio 0.67, 95% confidence interval 0.34–1.32).Conclusions:Sibutramine was associated with increased rates of acute cardiovascular events in people with pre-existing cardiovascular disease, but there was a low absolute risk in those without. Sibutramine’s marketing authorization may have, therefore, been inappropriately withdrawn for people without cardiovascular disease.

Admission to acute mental health services after contact with crisis resolution and home treatment teams: an investigation in two large mental health-care providers

BACKGROUND Crisis resolution and home treatment teams (CRTs) offer an alternative to hospital admission for patients undergoing mental health crises in the UK. Few studies have been done to examine predictors of relapse and readmission after contact with CRTs. METHODS We used the Clinical Record Interactive Search to identify all patients receiving care from CRTs in two National Health Service (NHS) mental health trusts in London: Camden and Islington NHS Foundation Trust and South London and Maudsley NHS Foundation Trust. We used Cox regression models to examine rates and predictors of admission to acute mental health services within 1 year of contact with CRTs. Sex, age, ethnicity, marital status, social deprivation, severity of psychopathology, duration of index CRT episode, first contact with services, and diagnosis were extracted and examined as predictors of admission. FINDINGS Between Jan 1, 2008, and Aug 31, 2014, 17 666 patients were treated by CRTs-8759 patients in the Camden and Islington trust and 8907 patients in the South London and Maudsley trust. 53·9 patients per 100 person-years (95% CI 52·1-55·8) in Camden and Islington and 51·3 patients per 100 person-years (95% CI 49·6-53·1) in South London and Maudsley were admitted to acute services within 1 year of seeing the CRT. In both cohorts, non-affective psychotic disorders (adjusted hazard ratio [HR] 1·25, 95% CI 1·09-1·44 in Camden and Islington; 1·27, 1·17-1·38 in South London and Maudsley) and age older than 65 years (1·18, 1·01-1·37 in Camden and Islington; 1·32, 1·12-1·56 in South London and Maudsley) were associated with increased risk of admission, whereas first contact with services (0·57, 0·52-0·62 in Camden and Islington; 0·69, 0·63-0·75 in South London and Maudsley), anxiety disorders (0·81, 0·69-0·96 in Camden and Islington; 0·77, 0·67-0·87 in South London and Maudsley), and longer index CRT episodes (adjusted HR per day 0·996, 0·994-0·998 in Camden and Islington; 0·989, 0·987-0·991 in South London and Maudsley) were associated with reduced risk of admission. INTERPRETATION Past use of mental health services and a diagnosis of non-affective psychosis, which are markers of severity of mental illness, and older age, which is a marker of chronicity, are all risk factors for future relapse after interactions with CRTs. These findings might help clinicians and policy makers to offer more targeted and cost-effective services to reduce relapse rates. FUNDING None.