Kyla H Thomas

Smoking cessation treatment and risk of depression, suicide, and self harm in the Clinical Practice Research Datalink: prospective cohort study

Objective To compare the risk of suicide, self harm, and depression in patients prescribed varenicline or bupropion with those prescribed nicotine replacement therapy. Design Prospective cohort study within the Clinical Practice Research Datalink. Setting 349 general practices in England. Participants 119 546 men and women aged 18 years and over who used a smoking cessation product between 1 September 2006 and 31 October 2011. There were 81 545 users of nicotine replacement products (68.2% of all users of smoking cessation medicines), 6741 bupropion (5.6%), and 31 260 varenicline (26.2%) users. Main outcome measures Outcomes were treated depression and fatal and non-fatal self harm within three months of the first smoking cessation prescription, determined from linkage with mortality data from the Office for National Statistics (for suicide) and Hospital Episode Statistics data (for hospital admissions relating to non-fatal self harm). Hazard ratios or risk differences were estimated using Cox multivariable regression models, propensity score matching, and instrumental variable analysis using physicians’ prescribing preferences as an instrument. Sensitivity analyses were performed for outcomes at six and nine months. Results We detected 92 cases of fatal and non-fatal self harm (326.5 events per 100 000 person years) and 1094 primary care records of treated depression (6963.3 per 100 000 person years). Cox regression analyses showed no evidence that patients prescribed varenicline had higher risks of fatal or non-fatal self harm (hazard ratio 0.88, 95% confidence interval 0.52 to 1.49) or treated depression (0.75, 0.65 to 0.87) compared with those prescribed nicotine replacement therapy. There was no evidence that patients prescribed bupropion had a higher risk of fatal or non-fatal self harm (0.83, 0.30 to 2.31) or of treated depression (0.63, 0.46 to 0.87) compared with patients prescribed nicotine replacement therapy. Similar findings were obtained using propensity score methods and instrumental variable analyses. Conclusions There is no evidence of an increased risk of suicidal behaviour in patients prescribed varenicline or bupropion compared with those prescribed nicotine replacement therapy. These findings should be reassuring for users and prescribers of smoking cessation medicines.

Risk of neuropsychiatric adverse events associated with varenicline: systematic review and meta-analysis

Objective To determine the risk of neuropsychiatric adverse events associated with use of varenicline compared with placebo in randomised controlled trials. Design Systematic review and meta-analysis comparing study effects using two summary estimates in fixed effects models, risk differences, and Peto odds ratios. Data sources Medline, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov. Eligibility criteria for selecting studies Randomised controlled trials with a placebo comparison group that reported on neuropsychiatric adverse events (depression, suicidal ideation, suicide attempt, suicide, insomnia, sleep disorders, abnormal dreams, somnolence, fatigue, anxiety) and death. Studies that did not involve human participants, did not use the maximum recommended dose of varenicline (1 mg twice daily), and were cross over trials were excluded. Results In the 39 randomised controlled trials (10 761 participants), there was no evidence of an increased risk of suicide or attempted suicide (odds ratio 1.67, 95% confidence interval 0.33 to 8.57), suicidal ideation (0.58, 0.28 to 1.20), depression (0.96, 0.75 to 1.22), irritability (0.98, 0.81 to 1.17), aggression (0.91, 0.52 to 1.59), or death (1.05, 0.47 to 2.38) in the varenicline users compared with placebo users. Varenicline was associated with an increased risk of sleep disorders (1.63, 1.29 to 2.07), insomnia (1.56, 1.36 to 1.78), abnormal dreams (2.38, 2.05 to 2.77), and fatigue (1.28, 1.06 to 1.55) but a reduced risk of anxiety (0.75, 0.61 to 0.93). Similar findings were observed when risk differences were reported. There was no evidence for a variation in depression and suicidal ideation by age group, sex, ethnicity, smoking status, presence or absence of psychiatric illness, and type of study sponsor (that is, pharmaceutical industry or other). Conclusions This meta-analysis found no evidence of an increased risk of suicide or attempted suicide, suicidal ideation, depression, or death with varenicline. These findings provide some reassurance for users and prescribers regarding the neuropsychiatric safety of varenicline. There was evidence that varenicline was associated with a higher risk of sleep problems such as insomnia and abnormal dreams. These side effects, however, are already well recognised. Systematic review registration PROSPERO 2014:CRD42014009224.

Suicide in England and Wales 1861–2007: a time-trends analysis

BACKGROUND Suicide is one of the leading causes of premature mortality worldwide. Few studies have assessed long-term trends or sex differences in its incidence over time. We have investigated the age-, sex- and method-specific trends in suicide in England and Wales from 1861 to 2007. METHODS Overall age-standardized suicide rates using the European Standard Population and age-, sex- and method-specific rates were calculated for ages ≥15 years from 1861 to 2007. RESULTS Rates in males were consistently higher than females throughout the 19th and 20th centuries, although the male-to-female sex ratio fluctuated from 4 : 1 in the 1880s to 1.5 : 1 in the 1960s. Suicide rates increased in all age groups in the 1930s, coinciding with the Great Depression. The highest male rates (30.3 per 100 000) were recorded in 1905 and 1934 and have since been declining. Female rates peaked in the 1960s (11.8 per 100 000), declining afterwards. In both sexes the lowest recorded rates were in the 21st century. There was a rapid rise in the use of domestic gas as a method of suicide in both sexes following its introduction at the end of the 19th century. There was no evidence that this rise was accompanied by a decline in the use of other methods. Self-poisoning also increased in popularity from the 1860s (5% of suicides) to the 1990s (22% of suicides). CONCLUSIONS The epidemiology of suicide in England and Wales has changed markedly over the past 146 years. The rapid rise in gas suicide deaths in the 1920s highlights how quickly a new method of suicide can be established in a population when it is easily available. The increase in suicides during the Great Depression has implications in relation to the current economic crisis. Changes in the acceptability and lethality of various suicide methods may account for the large variations in sex ratios over time.

Suicide epidemics: the impact of newly emerging methods on overall suicide rates - a time trends study

BackgroundThe impact of newly emerging, popular suicide methods on overall rates of suicide has not previously been investigated systematically. Understanding these effects may have important implications for public health surveillance. We examine the emergence of three novel methods of suicide by gassing in the 20th and 21st centuries and determine the impact of emerging methods on overall suicide rates.MethodsWe studied the epidemic rises in domestic coal gas (1919-1935, England and Wales), motor vehicle exhaust gas (1975-1992, England and Wales) and barbecue charcoal gas (1999-2006, Taiwan) suicide using Poisson and joinpoint regression models. Joinpoint regression uses contiguous linear segments and join points (points at which trends change) to describe trends in incidence.ResultsEpidemic increases in the use of new methods of suicide were generally associated with rises in overall suicide rates of between 23% and 71%. The recent epidemic of barbecue charcoal suicides in Taiwan was associated with the largest rise in overall rates (40-50% annual rise), whereas the smallest rise was seen for car exhaust gassing in England and Wales (7% annual rise). Joinpoint analyses were only feasible for car exhaust and charcoal burning suicides; these suggested an impact of the emergence of car exhaust suicides on overall suicide rates in both sexes in England and Wales. However there was no statistical evidence of a change in the already increasing overall suicide trends when charcoal burning suicides emerged in Taiwan, possibly due to the concurrent economic recession.ConclusionsRapid rises in the use of new sources of gas for suicide were generally associated with increases in overall suicide rates. Suicide prevention strategies should include strengthening local and national surveillance for early detection of novel suicide methods and implementation of effective media guidelines and other appropriate interventions to limit the spread of new methods.

Reporting of drug induced depression and fatal and non-fatal suicidal behaviour in the UK from 1998 to 2011

BackgroundPsychiatric adverse drug reactions (ADRs) are distressing for patients and have important public health implications. We identified the drugs with the most frequent spontaneous reports of depression, and fatal and non-fatal suicidal behaviour to the UK’s Yellow Card Scheme from 1998 to 2011.MethodsWe obtained Yellow Card data from the Medicines and Healthcare products Regulatory Agency for the drugs with the most frequent spontaneous reports of depression and suicidal behaviour from 1964 onwards. Prescribing data were obtained from the NHS Information Centre and the Department of Health. We examined the frequency of reports for drugs and estimated rates of reporting of psychiatric ADRs using prescribing data as proxy denominators from 1998 to 2011, as prescribing data were not available prior to 1998.ResultsThere were 110 different drugs with ≥ 20 reports of depression, 58 with ≥10 reports of non-fatal suicidal behaviour and 33 with ≥5 reports of fatal suicidal behaviour in the time period. The top five drugs with the most frequent reports of depression were the smoking cessation medicines varenicline and bupropion, followed by paroxetine (a selective serotonin reuptake inhibitor), isotretinoin (used in acne treatment) and rimonabant (a weight loss drug). Selective serotonin reuptake inhibitors, varenicline and the antipsychotic medicine clozapine were included in the top five medicines with the most frequent reports of fatal and non-fatal suicidal behaviour. Medicines with the highest reliably measured reporting rates of psychiatric ADRs per million prescriptions dispensed in the community included rimonabant, isotretinoin, mefloquine (an antimalarial), varenicline and bupropion. Robust denominators for community prescribing were not available for two drugs with five or more suicide reports, efavirenz (an antiretroviral medicine) and clozapine.ConclusionsDepression and suicide-related ADRs are reported for many nervous system and non-nervous system drugs. As spontaneous reports cannot be used to determine causality between the drug and the ADR, psychiatric ADRs which can cause significant public alarm should be specifically assessed and reported in all randomised controlled trials.

Association of socio-economic position and suicide/attempted suicide in low and middle income countries in South and South-East Asia – a systematic review

BackgroundForty percent of the world’s suicide deaths occur in low and middle income countries (LAMIC) in Asia. There is a recognition that social factors, such as socioeconomic position (SEP), play an important role in determining suicidal risk in high income countries, but less is known about the association in LAMIC.MethodsThe objective of this systematic review was to synthesise existing evidence of the association between SEP and attempted suicide/suicide risk in LAMIC countries in South and South East Asia. Web of Science, MEDLINE, MEDLINE in Process, EMBASE, PsycINFO, and article reference lists/forward citations were searched for eligible studies. Epidemiological studies reporting on the association of individual SEP with suicide and attempted suicide were included. Study quality was assessed using an adapted rating tool and a narrative synthesis was conducted.ResultsThirty-one studies from nine countries were identified; 31 different measures of SEP were reported, with education being the most frequently recorded. Most studies suggest that lower levels of SEP are associated with an increased risk of suicide/attempted suicide, though findings are not always consistent between and within countries. Over half of the studies included in this review were of moderate/low quality. The SEP risk factors with the most consistent association across studies were asset based measures (e.g. composite measures); education; measures of financial difficulty and subjective measures of financial circumstance. Several studies show a greater than threefold increased risk in lower SEP groups with the largest and most consistent association with subjective measures of financial circumstance.ConclusionThe current evidence suggests that lower SEP increases the likelihood of suicide/attempted suicide in LAMIC in South and South East Asia. However, the findings are severely limited by study quality; larger better quality studies are therefore needed.Systematic review registrationPROSPERO 2014:CRD42014006521

Changes in commonly used methods of suicide in England and Wales from 1901-1907 to 2001-2007

OBJECTIVE To investigate changes in the range of suicide methods used in two time periods a century apart (1901-1907 and 2001-2007) in England and Wales. METHOD Suicide mortality and population data were obtained for England and Wales from the ONS and used to calculate gender and method-specific mortality rates. RESULTS There have been striking changes in the methods of suicide used since the 1900s. Hanging was the most commonly used method during both time periods. However suicides involving drowning (22.5% of suicides in 1901-1907) and weapons (e.g. firearms and razors, 24.2% of suicides in 1901-1907) were rarely used in 2001-2007 (2.6% and 5.8% respectively). Although the use of poisons was popular in both time periods, the types of poisons used differed substantially over time. Household cleaning products and disinfectants accounted for almost half of poisoning suicides in the early 1900s whereas self-poisoning with medicines accounted for most poisoning suicides in 2001-2007. LIMITATIONS There were changes in the coding of suicides over time. Additionally, deaths by drowning and poisoning are more difficult to confirm as suicides than those that occur due to hanging or the use of weapons. CONCLUSIONS The changes in popularity of some suicide methods can be mainly attributed to changes in the physical availability (access) of these methods over time. Other methods which remain readily available have fallen out of fashion in recent times, suggesting a contributory role of other factors such as cognitive availability and personal preference/acceptability in influencing the choice of suicide method.

Self-cutting and risk of subsequent suicide

BACKGROUND Some studies suggest that people who self-cut have a higher risk of suicide than those who self-poison. Self-cutting ranges from superficial wrist cutting to severe self-injury involving areas such as the chest, abdomen and neck which can be life threatening. This study aimed to investigate whether the site of self-cutting was associated with risk of subsequent suicide. METHODS We followed-up 3928 people who presented to hospital following self-harm between September 2010 and December 2013 in a prospective cohort study based on the Bristol Self-harm Surveillance Register. Demographic information from these presentations was linked with coroners data to identify subsequent suicides. RESULTS People who presented with self-cutting to areas other than the arm/wrist were at increased risk of suicide compared to those who self-poisoned (HR 4.31, 95% CI 1.27-14.63, p=0.029) and this increased risk remained after controlling for age, sex, history of previous self-harm and psychiatric diagnosis (HR 4.46, 95% CI 1.50-13.25, p<0.001). We observed no such increased risk in people presenting with cutting to the arm/wrist. LIMITATIONS These data represent the experience of one city in the UK and may not be generalisable outside of this context. Furthermore, as suicide is a rare outcome the precision of our estimates is limited. CONCLUSIONS Site of self-injury may be an important indicator of subsequent suicide risk.

The effectiveness of varenicline versus nicotine replacement therapy on long-term smoking cessation in primary care: a prospective cohort study of electronic medical records

Abstract Background There is limited evidence about the effectiveness of varenicline and nicotine replacement therapy (NRT) for long-term smoking cessation in primary care, or whether the treatment effectiveness differs by socioeconomic position (SEP). Therefore, we estimated the long-term effectiveness of varenicline versus NRT (> 2 years) on smoking cessation, and investigated whether effectiveness differs by SEP. Methods This is a prospective cohort study of electronic medical records from 654 general practices in England, within the Clinical Practice Research Datalink, using three different analytical methods: multivariable logistic regression, propensity score matching and instrumental variable analyses. Exposure was prescription of varenicline versus NRT, and the primary outcome was smoking cessation at 2 years’ follow-up; outcome was also assessed at 3, 6, and 9 months, and at 1 and 4 years after exposure. SEP was defined using the Index of Multiple Deprivation. Results At 2 years, 28.8% (N = 20 362/70 610) of participants prescribed varenicline and 24.3% (N = 36 268/149 526) of those prescribed NRT quit; adjusted odds ratio was 1.26 [95% confidence interval (CI): 1.23 to 1.29], P < 0.0001. The association persisted for up to 4 years and was consistent across all analyses. We found little evidence that the effectiveness of varenicline differed greatly by SEP. However, patients from areas of higher deprivation were less likely to be prescribed varenicline; adjusted odds ratio was 0.91 (95% CI: 0.90 to 0.92), P < 0.0001. Conclusions Patients prescribed varenicline were more likely to be abstinent up to 4 years after first prescription than those prescribed NRT. In combination with other evidence, the results from this study may be used to update clinical guidelines on the use of varenicline for smoking cessation.

How to compare instrumental variable and conventional regression analyses using negative controls and bias plots

Abstract There is increasing interest in the use of instrumental variable analysis to overcome unmeasured confounding in observational pharmacoepidemiological studies. This is partly because instrumental variable analyses are potentially less biased than conventional regression analyses. However, instrumental variable analyses are less precise, and regulators and clinicians find it difficult to interpret conflicting evidence from instrumental variable compared with conventional regression analyses. In this paper, we describe three techniques to assess which approach (instrumental variable versus conventional regression analyses) is least biased. These techniques are negative control outcomes, negative control populations and tests of covariate balance. We illustrate these methods using an analysis of the effects of smoking cessation therapies (varenicline) prescribed in primary care.