Multiple RCTs have evaluated the efficacy of many of the SGAs in paediatric mental health disorders. These medications have been a useful addition to the treatment options available for a number of paediatric mental health disorders. These benefits, however, do not come without risks: both metabolic and neurological side effects occur in children treated with these SGAs. The risk of weight gain, increased BMI and abnormal lipid levels is greatest with olanzapine, followed by clozapine and quetiapine. The risk of neurological side effects of treatment is greatest with risperidone, olanzapine and aripiprazole. Neurological side effects are very uncommon in children treated with quetiapine and clozapine; not enough paediatric data on ziprasidone exists to draw a conclusion.
The present guidelines specifically focused on metabolic and neurological side effects, and how they should be monitored. SGAs can cause other side effects that were not discussed in the present article including sedation, drooling, a decrease in absolute neutrophil count (with clozapine), cataracts (with quetiapine) and prolongation of the QTc interval. Clinicians prescribing these medications should familiarize themselves with the most common adverse events associated with the SGA they are prescribing, and consult appropriate resources on when to perform absolute neutrophil counts (5
), electrocardiograms (4
) and slit lamp eye examinations (6
). Users of these guidelines should be aware that we have also created separate guidelines on the management of SGA-related metabolic and neurological complications that are detected over the course of monitoring procedures.
With respect to the noted metabolic side effects of SGA treatment, the long-term health consequences of obesity and dyslipidemia in children are concerning. Higher BMI during childhood is associated with an increased risk of coronary artery disease in adulthood (11
). A prospective cohort study of 2195 children followed for 21 years (12
) showed that youth determinants of adult metabolic syndrome include obesity, and high triglyceride, insulin and C-reactive protein levels, as well as a family history of hypertension and type 2 diabetes. Obesity, high low-density lipoprotein cholesterol and low high-density lipoprotein cholesterol in childhood are associated with a decrease in carotid artery elasticity in adulthood – an early pathophysiological change relevant to the development of atherosclerosis (13
). The social and emotional consequences of obesity in a child who may already be seen as different due to his/her mental health disorder is also worth considering. A prospective study demonstrated that women with childhood metabolic syndrome showed higher levels of depressive symptoms in adulthood than women who did not have childhood metabolic syndrome (14
Given the evidence for metabolic side effects in children treated with SGAs, and the long-term sequelae of these problems, monitoring of all children who are prescribed SGAs is appropriate. There has been a notable lag, however, in translation of the research evidence into changes in clinical practice. Data from the United States suggest that metabolic testing rates have showed little change following the 2003 Food and Drug Administration warning on diabetes risk for SGAs and recommendations from the American Diabetes Association and American Psychiatric Association (15
) in 2004 that all patients receiving SGAs undergo glucose and lipid testing. In the evaluation of 109,451 individuals receiving Medicaid who began taking an SGA (sample included 25% children), initial testing rates (prewarning) were low (glucose 27% and lipids 10%). The Food and Drug Administration warning and the American Diabetes Association/American Psychiatric Association recommendations were not associated with an increase in glucose testing among SGA-treated patients, and was associated with only a marginal increase in lipid testing rates (1.7% [P<0.02]) (16
We have attempted to create an evidence-based monitoring protocol for physicians to follow when prescribing an SGA to a child with a mental health condition. Because the risk of metabolic and neurological side effects varies between SGA medications, we have provided the levels of evidence associated with the specific side effects of each drug. While this adds a layer of complexity for physicians to follow, there are important differences in the side effect profiles of the SGAs that should be noted. Monitoring summary tables for physical examination manoeuvres and laboratory tests with recommendation grades according to each individual SGA have been created ( and ). Recognizing that some clinicians may not have adequate resources to apply these drug-specific recommendations, we have also created a simplified single-screening and monitoring tool () for ease of use in the clinical setting. The entire Metabolic Assessment, Screening and Monitoring Tool (from which has been extracted) is available online (http://keltymentalhealth.ca/partner/provincial-mental-health-metabolic-program
) under the Resources tab.
A practical tool for metabolic monitoring of children and youth treated with second-generation antipsychotics
Experience suggests that, in situations in which an SGA is recommended, the average number of SGAs trialed for a given patient is between two to three (unpublished data). As a result, it is important to complete full baseline measurements on patients receiving any one of the SGAs. Notable in is the recommendation to complete a clinical assessment including physical examination manoeuvres such as height, weight, waist circumference, and blood pressure at four and eight weeks following initiation of the SGA. In addition to determining effectiveness of the medications following their initiation, careful monitoring at these time points is necessary given the current evidence, which suggests that significant changes may occur in weight and waist circumference within four weeks of initiating SGAs (17
). Early intervention with conservative lifestyle measurements, if weight and/or waist circumference increase within the first three months of treatment with an SGA, may mitigate these metabolic side effects.
Prolactin monitoring is recommended after three months of treatment with risperidone or olanzapine, and after six months with ziprasidone and, if normal, on a yearly basis thereafter in asymptomatic children. This is because prepubertal children may not develop clinical symptoms or signs of hyperprolactinemia (menstrual irregularity, gynecomastia or galactorrhea); the long-term consequences of chronic elevation of prolactin levels on future sexual, bone and breast development are unknown. While there is evidence to suggest that prolactin levels may normalize over time in children on chronic treatment (18
), this is not always the case; therefore, we have adopted a conservative stance until further information is available. Prolactin undergoes diurnal fluctuations, and can be altered by medication (20
) and food intake. Prolactin levels should, therefore, be determined after fasting with scheduled blood work – some of which also requires a 12 h fast (eg, blood lipids). Because we found no evidence of abnormalities in the electrolytes or renal function tests, such as urea or creatinine, with the use of SGAs, we have not made any screening recommendations for these tests as a part of routine monitoring of SGA safety.
We have not made evidence-based recommendations for monitoring beyond one year due to the lack of long-term studies. As more information becomes available from long-term prospective cohort studies, we expect this evidence will be used to inform practice. At this time, we recommend that clinicians use their clinical judgment to make decisions about monitoring children beyond one year of treatment based on the results of their monitoring to date. Beyond the first year of monitoring, it is the clinical practice of the members of our guideline group to repeat laboratory tests yearly in stable patients with a normal physical examination and previous normal laboratory tests. Physical examination manoeuvres are completed during all follow-up visits as a part of routine care.
We recognize that there may be organizational barriers to applying the recommendations of these guidelines. Clinicians have a number of demands on their time; the need to perform specific physical examination manoeuvers and laboratory tests will add time to clinical visits. We advise that, given the good evidence for specific metabolic and neurological side effects associated with SGAs, clinicians who are unprepared to monitor children for side effects should choose not to prescribe these medications. A website is currently under construction (www.camesaguideline.org
), which will include downloadable forms for physicians to help facilitate adoption of the recommendations. While there are cost implications with respect to the use of laboratory tests for monitoring safety, we believe that the cost of these preventive measures will be far less than the costs of managing the long-term effects of obesity and hyperlipidemia in cardiovascular disease.
We anticipate that the use of these evidence-based guidelines on monitoring SGA safety in children will improve the quality of care of children with mental health disorders, and help improve awareness among patients and practitioners of the side effects associated with these drugs.