• Cardiovascular Risk of Concomitant Use of Atypical Antipsychotics and Stimulants Among Commercially Insured Youth in the United States

      Zhang, Chengchen; Spence, O'Mareen; Reeves, Gloria; dosReis, Susan (Frontiers Media S.A., 2021-04-29)
      Objectives: To investigate the risk of cardiovascular events associated with concomitant use of stimulants and atypical antipsychotics (AAPs) among youth and evaluate whether AAP dose and duration of concomitant use modifies the risk. Methods: We used IQVIA PharMetrics® Plus data from 2006 to 2015 to construct a retrospective cohort of commercially-insured youth aged 5-17 years old who initiated a stimulant medication. Time-varying concomitant stimulant/AAP use was defined as current, past and no concomitant use based on person months. The primary time-varying Cox proportional hazard regression analysis evaluated the risk of cardiovascular events comparing current concomitant use with past and no concomitant use, adjusted for baseline cardiovascular risk. A secondary analysis assessed the risk of cardiovascular events comparing AAP daily doses (<1, 1-2, >2 mg) and duration (<3, 3-6, >6 months) of current concomitant use to no concomitant use. Cardiovascular outcomes included severe (i.e., stroke, acute myocardial infarction, ischemic heart disease) and less severe (i.e., angina pectoris, cardiac dysrhythmias, transient cerebral ischemia, hypertensive disease, tachycardia, palpitations, syncope). Results: For this cohort of 61,438 youths, the incidence rate of severe cardiovascular events was 0.18 per 10,000 person-months, and all events occurred in no concomitant use months. The risk of less severe cardiovascular events was significantly higher in current concomitant users compared with no [HR: 2.59 (95%CI: 1.72, 3.90)] and past [HR: 1.89 (95%CI: 1.10, 3.24)] concomitant users. Compared to no concomitant use, the risk of less severe cardiovascular events was significantly higher at all AAP daily doses [HR: <1 mg: 2.82 (95%CI: 1.72, 4.61); 1-2 mg: 2.22 (95%CI: 1.16, 4.25); >2 mg: 2.65 (95%CI: 1.50, 4.71)]. The risk of less severe cardiovascular events significantly elevated for all duration of use and was higher for <3 months of concomitant use [HR: <3 months: 3.45 (95%CI: 2.17, 5.47) relative to 3-6 months: 2.60 (95%CI: 1.29, 5.25) or >6 months: 2.61 (95%CI: 1.59, 4.30)]. Conclusions: Severe cardiovascular events are rare. Concomitant stimulant/AAP use elevates the risk of less severe cardiovascular events. Periodic heart rate or blood pressure monitoring for youth on stimulant/AAP treatment may be warranted.
    • Metformin add-on vs. antipsychotic switch vs. continued antipsychotic treatment plus healthy lifestyle education in overweight or obese youth with severe mental illness: results from the IMPACT trial

      Reeves, G.; Pirmohamed, S.; Edwards, S. (Blackwell Publishing Ltd, 2020)
      Antipsychotics are used for many psychiatric conditions in youth. Although developmentally inappropriate weight gain and metabolic abnormalities, which are risk factors for premature cardiovascular mortality, are especially frequent in youth, optimal strategies to reduce pediatric antipsychotic‐induced overweight/obesity are unclear. The Improving Metabolic Parameters in Antipsychotic Child Treatment (IMPACT) was a randomized, parallel group, 24‐week clinical trial which enrolled overweight/obese, psychiatrically stable youth, aged 8‐19 years, with a DSM‐IV diagnosis of severe mental illness (schizophrenia spectrum disorder, bipolar spectrum disorder or psychotic depression), at four US universities. All of them had developed substantial weight gain following treatment with a second‐generation antipsychotic. The centralized, computer‐based randomization system assigned participants to unmasked treatment groups: metformin (MET); antipsychotic switch (aripiprazole or, if already exposed to that drug, perphenazine or molindone; SWITCH); or continued baseline antipsychotic (CONTROL). All participants received healthy lifestyle education. The primary outcome was body mass index (BMI) z‐score change from baseline, analyzed using estimated least squares means. Altogether, 127 participants were randomized: 49 to MET, 31 to SWITCH, and 47 to CONTROL. BMI z‐score decreased significantly with MET (week 24: –0.09±0.03, p=0.002) and SWITCH (week 24: –0.11±0.04, p=0.003), while it increased non‐significantly with CONTROL (week 24: +0.04±0.03). On 3‐way comparison, BMI z‐score changes differed significantly (p=0.001). MET and SWITCH were each superior to CONTROL (p=0.002), with effect sizes of 0.68 and 0.81 respectively, while MET and SWITCH did not differ. More gastrointestinal problems occurred in MET than in SWITCH or CONTROL. The data safety monitoring board closed the perphenazine‐SWITCH arm because 35.2% of subjects discontinued treatment due to psychiatric worsening. These data suggest that pediatric antipsychotic‐related overweight/obesity can be reduced by adding metformin or switching to a lower risk antipsychotic. Healthy lifestyle education is not sufficient to prevent ongoing BMI z‐score increase.