RESEARCH Antidepressant utilisation and incidence of weight gain during 10 years’ follow-up: population based cohort study BMJ: first published as 10.1136/bmj.k1951 on 23 May 2018. Downloaded from Rafael Gafoor,1 Helen P Booth,1,2 Martin C Gulliford1,3 1School of Population Health ABSTRACT rate ratio for transition to overweight or obesity was and Environmental Sciences, OBJECTIVE 1.29 (1.25 to 1.34); in people who were initially King’s College London, London To evaluate the long term association between overweight, the adjusted rate ratio for transition to SE1 1UL, UK antidepressant prescribing and body weight. obesity was 1.29 (1.25 to 1.33). Associations may not 2Clinical Practice Research Datalink, Medicines and DESIGN be causal, and residual confounding might contribute Healthcare products Regulatory Population based cohort study. to overestimation of associations. Agency, London, UK CONCLUSION 3NIHR Biomedical Research SETTING Centre at Guy’s and St Thomas’ General practices contributing to the UK Clinical Widespread utilisation of antidepressants may be NHS Foundation Trust and Practice Research Datalink, 2004-14. contributing to long term increased risk of weight King’s College London, Guy’s gain at population level. The potential for weight gain PARTICIPANTS Hospital, London, UK should be considered when antidepressant treatment 136 762 men and 157 957 women with three or more Correspondence to: R Gafoor is indicated. [email protected] records for body mass index (BMI). Additional material is published online only. To view please visit MAIN OUTCOME MEASURES the journal online. The main outcomes were antidepressant prescribing, Introduction Cite this as: BMJ 2018;361:k1951 incidence of ≥5% increase in body weight, and Obesity is an increasing concern worldwide. Between http://dx.doi.org/10.1136/bmj.k1951 transition to overweight or obesity. Adjusted rate 1975 and 2014 the global prevalence of obesity Accepted: 13 April 2018 ratios were estimated from a Poisson model adjusting increased from 3.2% to 10.8% for men and from 6.4% for age, sex, depression recording, comorbidity, to 14.9% for women.1 The United States and United coprescribing of antiepileptics or antipsychotics, Kingdom have among the highest rates of obesity in the deprivation, smoking, and advice on diet. world: 69% of US adults are overweight or obese and 2 RESULTS 36% are obese, and 61% of UK adults are overweight In the year of study entry, 17 803 (13.0%) men and or obese, with the prevalence of obesity increasing 3 35 307 (22.4%) women with a mean age of 51.5 years from 15% in 1993 to 26% in 2016. Severe obesity is http://www.bmj.com/ (SD 16.6 years) were prescribed antidepressants. strongly associated with socioeconomic inequality in During 1 836 452 person years of follow-up, the both the US and the UK.4 Weight gain and obesity are incidence of new episodes of ≥5 weight gain in important public health problems, being associated participants not prescribed antidepressants was 8.1 with increased risk of chronic disease and mortality.5 6 per 100 person years and in participants prescribed Once obesity is established, it is difficult to achieve antidepressants was 11.2 per 100 person years substantial and sustained weight loss.7 (adjusted rate ratio 1.21, 95% confidence interval Antidepressants are increasingly being prescribed.8 on 2 October 2021 by guest. Protected copyright. 1.19 to 1.22, P<0.001). The risk of weight gain In a primary care population 23% of 1.5 million remained increased during at least six years of follow- participants were prescribed an antidepressant on up. In the second year of treatment the number of at least one occasion between 1995 to 2011.9 The participants treated with antidepressants for one number of antidepressant prescriptions issued nearly year for one additional episode of ≥5% weight gain doubled over the same period, although some of the was 27 (95% confidence interval 25 to 29). In people increase might be explained by extended duration who were initially of normal weight, the adjusted of courses of treatment.9 Obesity is associated with depression, which is particularly common in patients with severe obesity.10 11 Antidepressant treatment WHat IS ALREADY KNOWN ON THIS TOPIC may also be associated with weight gain,12 through 13 Obesity is global and antidepressant use is increasingly widespread mechanisms that are only partially understood. The Short term studies suggest strong associations between antidepressant use and current high prevalence of antidepressant use could weight gain have potentially important public health impacts through the association with body weight gain, but No robust data exist on the long term risks of weight gain or the relative risks of the nature of this association is poorly described. weight gain for individual antidepressants Although a systematic review of antidepressant use WHat THIS stUDY ADDS and weight gain collated evidence from 116 clinical 14 Antidepressant treatment is associated with a sustained increase in risk of trials and clinical cohort studies, fewer than half weight gain over at least five years of the studies contributed data for more than three months of follow-up and it was not reported how many Associations with subsequent weight gain appear to vary widely within and studies included more than 12 months of follow-up. between antidepressant classes The review also drew attention to the heterogeneity Risk of weight gain should be considered when antidepressants are to be among different antidepressant drugs, with bupropion prescribed and fluoxetine being associated with lower weight gain the bmj | BMJ 2018;361:k1951 | doi: 10.1136/bmj.k1951 1 RESEARCH than mirtazapine and nortriptyline.14 Most studies we selected a random sample of up to a maximum of have reported on weight change in depressed patients 30 000 participants from each category of BMI and sex, BMJ: first published as 10.1136/bmj.k1951 on 23 May 2018. Downloaded from treated in clinical settings, but few population based resulting in 314 477 participants, for whom data were studies have investigated the potential population extracted for 314 449 participants. Fewer than 30 000 impact of widespread antidepressant treatment on women had a BMI of ≥45 and fewer than 30 000 men weight gain. One study evaluated weight change had a BMI of ≥40. We then extracted full CPRD records after initiation of antidepressant treatment in 5932 for this sample. In the analysis phase we computed patients registered with the Group Health system in additional BMI values from recorded weight and Washington state, USA, and found that weight gain height, permitting a greater number of participants to persisted for at least two years.15 A UK study analysed be represented in some BMI categories. We excluded data for 268 patients treated with antidepressants from participants with no BMI records for 1 November 2004 a general practice with 11 994 registered patients, to 31 October 2014. and concluded that weight gain persisted during long term treatment, with, in some instances, prescriptions Main outcome measures maintained for several years.16 Another US study Antidepressant prescriptions were the exposure evaluated weight gain in the 12 months after initiation of interest. We initially classified these according of antidepressant treatment in 22 610 adults treated to section 4.3 of the British National Formulary,20 in clinics in New England and found differences in the including tricyclic and related antidepressants (TCAs), propensity of individual antidepressants to result in monoamine oxidase inhibitors (MAOIs), selective weight gain.17 serotonin reuptake inhibitors (SSRIs), serotonin- In this study we used primary care electronic health noradrenaline (norepinephrine) reuptake inhibitors records to evaluate non-randomised evidence on the (SNRIs), and other antidepressant drugs. We then long term association of antidepressant prescribing analysed individual antidepressant drugs: mirtazapine, with weight gain. We also evaluated the associations duloxetine, sertraline, venlafaxine, citalopram, in different subgroups and whether individual fluoxetine, escitalopram, trazodone, amitriptyline, antidepressant drugs might be associated with greater paroxetine, nortriptyline, and dosulepin. risks of weight gain. Body weight was the outcome of interest. We evaluated all records of body weight, height, and BMI. Methods If a body weight value was recorded that indicated a ≥ Data source weight increase of 5% compared with the previous http://www.bmj.com/ We carried out a population based cohort study in the year, we classified the calendar year as being associated UK Clinical Practice Research Datalink (CPRD). The with weight gain. In the analysis we retained person CPRD is one of the world’s largest databases of primary time not associated with recorded body weight values, care electronic health records, with participation incorporating the assumption that weight gain had of about 7% of UK general practices and with not occurred. In a sensitivity analysis, we excluded ongoing collection of anonymised data from 1990. person time with no weight records, so as to provide a The registered active CPRD population is generally “complete case” analysis. on 2 October 2021 by guest. Protected copyright. representative of the UK population in terms of age, We included several variables as known sex, and regional distribution.18 During 2004-14, confounders or effect modifiers in the relation between the annual count of the CPRD registered