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Monograph - Download PDF Introduction When treating children and adolescents, clinicians need to carefully consider the risk-benefit ratio of the treatments they choose. This is particularly pertinent for atypical antipsychotics, a class of medications that is being used increasingly in children and adolescents. To improve outcomes, clinicians need to consider the efficacy of antipsychotics as well as the health implications of weight gain, related metabolic issues and endocrine abnormalities that can be associated with antipsychotic treatment. Second-generation antipsychotics are frequently considered as a medication class in children. However, there is a growing awareness that second-generation antipsychotics differ considerably regarding their potential to cause weight gain, as well as metabolic and endocrine abnormalities with considerable impact on long-term psychological and physical health within the child and adolescent population. This monograph reviews the prevalence of metabolic and endocrine abnormalities in children and adolescents, as well as the effects that antipsychotic treatment can have on body weight, metabolic and endocrine parameters, such as glucose, insulin, lipids, and prolactin. Additionally, an expert faculty discusses monitoring and intervention strategies in order to improve metabolic and endocrine health for those children and adolescents who require antipsychotic treatment. Relationship between Obesity and Metabolic Abnormalities The increased incidence of childhood overweight and obesity is a global phenomenon. In the United States, during the period from 1980 to 2002, the percentage of overweight children aged 6-11 increased from 7% to 16% (128% increase) and the percentage of overweight children aged 12-19 increased from 5% to 16% (220% increase).1-3 Prevalence data show that children in both developed and developing countries are at risk for being overweight or obese.4 Numerous metabolic abnormalities are associated with weight gain
and obesity. Increased adiposity (i.e, intravisceral fat) associated with
weight gain leads to increased lipolysis of triglycerides which, in turn,
increases free fatty acid (FFA) levels. Increased oxidation of FFAs can alter
glucose metabolism and lipid profiles producing insulin resistance, as well Moreover, insulin resistance associated with obesity and age-inappropriate weight gain increases the risk for the development of type 2 diabetes.6 Increased body weight, glucose and lipid levels are continuous risk factors for adverse health events; although pathological thresholds have been proposed, any increase in these measures, even within the normal range, is associated with negative effects on health and survival.7 Excessive weight gain in childhood and obesity are associated with a variety of adverse health effects that may influence the development of comorbidities in adulthood. Multiple complications include psychosocial, pulmonary, gastrointestinal, renal, musculoskeletal, endocrine, cardiovascular, and neurological consequences.4 Metabolic and endocrine effects include type 2 diabetes, precocious puberty, polycystic ovary syndrome in girls, and hypogonadism in boys. Weight gain is more than a cosmetic issue; childhood obesity also predicts obesity, metabolic syndrome, 8-11 coronary artery disease and colorectal cancer in adulthood.12,13 In children with psychiatric illnesses, the psychiatric disorder itself, its treatment, and individual patient behavior may all contribute to the risk of developing overweight and comorbidities. The overall risk in youth may be compounded when disease and treatment-related factors are superimposed on background societal increases in childhood overweight and obesity. Relationship Between Metabolic Abnormalities and Psychiatric Illness An increased risk of developing metabolic and endocrine abnormalities in people with major psychiatric disorders may be related to the disease itself. The risk of diabetes may be inherently higher in some populations with schizophrenia or bipolar disorder.14 Disease-related lifestyle factors, such as poor nutrition and substance abuse, also contribute to the risk of weight gain and metabolic complications. In the case of children and adolescents, physical and mental symptoms, fatigue, sedation and extrapyramidal symptoms all may reduce the level of physical activity. In addition, childhood obesity negatively impacts self-esteem and may, in turn, negatively impact medication adherence. Psychiatrists may have more contact with a youngster suffering from a serious psychiatric ailment than other medical professionals, thus it is incumbent upon them to consider how the patient’s treatment and status can influence weight and metabolic parameters. In adults, studies show that even a relatively small reduction in weight reduces the risk of diabetes and coronary heart disease.15,16 In order to improve physical health, clinicians should set the same standard for youngsters with psychiatric illness as they do for the general population. It is important that everyone involved in the care and treatment of children with mental illness pay attention to the child’s medical, emotional, and behavioral situation in order to optimize treatment outcomes. Atypical antipsychotic effects on weight, metabolic Indices, and endocrine parameters Psychiatric medications, including atypical antipsychotics, have been associated with changes in weight, metabolic indices, and endocrine parameters. Potential treatment-related effects include weight gain, diabetes, hyperlipidemia, hyperprolactinemia, and cardiovascular disease.17Reasons for weight gain and associated metabolic complications are complex, but include factors related to the underlying psychiatric illness, poor health behaviors and psychiatric treatments, including increased appetite and food intake, sedation and extrapyramidal symptoms.14 There is increasing evidence that some antipsychotics may also alter glucose metabolism and induce insulin resistance directly, independent of weight gain.18,19 Weight and Metabolic Indices Weight gain with second-generation antipsychotics has been reported in multiple studies and may affect children and adolescents to a greater degree than adults.17
However, other psychiatric medications used in combination with antipsychotics can also have effects on weight. A pooled analysis of 11 short-term studies of 433 youngsters (mean age 12.3 years) with bipolar disorder showed that combined antipsychotic-mood stabilizer treatment may increase weight gain compared to antipsychotic treatment alone.20 Patients treated with a combination of an antipsychotic and a mood stabilizer had significantly greater weight gain (5.5%) compared to patients treated with a mood stabilizer alone, both including topiramate (n=171; mean weight gain 1.2%) or excluding topiramate (n=142; mean weight gain 1.8%), which has been associated with weight loss. Moreover, the weight gain of the atypical antipsychotic-mood stabilizer combination treatment was significantly greater than co-treatment with 2 mood stabilizers (n=128; mean weight gain 2.1%) and numerically greater than with one atypical antipsychotic (n=105; mean weight gain 3.4%). On the other hand, weight change data from a study of patients with autism treated with risperidone suggest that cotreatment with psychostimulants for attention deficit-hyperactivity disorder may not significantly attenuate weight gain.21 Data from risperidone treatment in autistic children further suggest that the rate of weight gain may decrease over time.22,23 While all of the atypical antipsychotics can promote weight gain, especially in drug-naïve youngsters, they are not equivalent in their ability to do so. Studies suggest that the tendency to promote weight gain (most to least) can be organized as clozapine=olanzapine>>risperidone≥ quetiapine>ziprasidone ≥ aripiprazole.17 As discussed above, insulin increases may precede glucose increases and signal subclinical metabolic changes. Insulin resistance is at the center of the pathophysiology of the metabolic syndrome, which is defined by having at least 3 of the following 5 features: abdominal obesity, dyslipidemia (i.e., hypertriglyceridemia and low high-density lipoprotein), hyperglycemia, and hypertension.24. In youngsters, age, height, and gender all influence the normal values of parameters associated with the metabolic syndrome, therefore, clinicians need to refer to age- and sex-adjusted references when evaluating youngsters.17 Hyperprolactinemia Treatment with conventional antipsychotics often increases serum prolactin levels. Similar increases are absent with many atypical antipsychotics; this is believed to be due to decreased blockage of dopamine receptors in the tubero-infundibular pathway at therapeutic doses. It is important to recognize that the long-term consequences of hyperprolactinemia are not well known. Most of the information about hyperprolactinemia comes from studies of patients with pituitary adenomas that increase prolactin levels into the tens of thousands. In comparison, antipsychotic treatment may increase prolactin levels into the low one hundreds. Increased prolactin levels have been associated with amenorrhea, oligomenorrhea, breast enlargement (males and females), galactorrhea, decreased libido, erectile dysfunction, osteoporosis secondary to hypogonadism, failure to enter or progress through puberty, hirsutism in females, and possible relationship to benign pituitary tumors.17 In pre-pubescent children, it can be difficult to evaluate adverse sexual and reproductive system effects because they are not sexually mature. As for weight gain and metabolic adverse effects, discussions of long-term effects of increased prolactin should take into consideration the level of evidence for negative health outcomes, as well as the impact of the untreated or under-treated psychiatric illness. In summary, the development of metabolic and endocrine side effects can negatively impact health and psychiatric outcomes, as well as treatment adherence. Therefore, when developing treatment regimens, it is important to consider the individual patient and to balance the efficacy with the side effect profiles of available agents.
Monitoring and Intervention Strategies to Minimize Side Effects What should clinicians, including psychiatric professionals, measure in children and adolescents who are treated with antipsychotics? A personal and family medical history is vital. This can indicate if the youngster has a prior history of weight gain, or a family history of diabetes or hyperlipidemia, which can increase the risk of metabolic effects. In addition, an assessment of lifestyle behaviors (i.e., diet, exercise and smoking) should be done at baseline and at each visit to identify potential risk factors and barriers to effective treatment. Baseline values (i.e., prior to starting an antipsychotic medication) should be obtained for weight, height, BMI, blood pressure, fasting plasma glucose and fasting plasma lipids. During the initial phase of treatment, it is recommended that weight be assessed every four weeks, since in adults, early weight gain was a very strong predictor of subsequent weight gain.25 At 3 months and at least annually, all information and assessments obtained at baseline should be repeated to assure patient health during antipsychotic treatment. Because children and adolescents appear to be more sensitive to weight gain and metabolic abnormalities, fasting glucose and lipids may need to be assessed every 6 months to provide optimal monitoring. A suggested schedule of assessments recommended by the American Diabetes Association is outlined in Table 1.
Body Mass Index Weight and body mass index, which can be measured easily by anyone who treats the youngster, are the parameters of greatest interest. The BMI can be calculated using either of the following formulas: BMI = (weight in kg) / (height in meters)2 However, it is important for clinicians to remember that a normal
body mass index changes across the life cycle and the thresholds are different
in youngsters than in adults. Values that fall within an average relative
growth curve at one point in life might be not average at another. Therefore,
youngsters are monitored relative to BMI percentiles that take sex and age into
consideration, rather than individual BMI cutoff values. Generally, youngsters
who fall within the 85th to 94th percentile are considered at risk for being
overweight. Youngsters who are above the 95th percentile for their gender and
given age are overweight or obese. (Box 1) The BMI percentile (used to
determine weight status) and the BMI z-score (used to track sex- and
age-adjusted BMI values over time, adjusting for age-appropriate weight gain)
can be calculated using simple tools or online resources
Laboratory Values Key laboratory parameters include glucose, lipids and insulin; fasting levels are optimal. It is recommended that fasting glucose and lipid values be evaluated at baseline, 3 months and at least annually, with more frequent assessments in patients with risk factors for metabolic abnormalities (e.g., family history, minority ethnicity, significant weight gain).26 (Table 1) In children and adolescents, 6-monthly fasting blood work may be indicated for optimal monitoring. While routine insulin assessments are not currently recommended, they enable a more careful assessment of the development of insulin resistance, which predates abnormalities in fasting glucose by many years. It is important to establish a baseline and monitor levels over time to evaluate trends, rather than using a single time point measurement. Of note, lipid level cutoffs are lower in youngsters than in adults. In addition, some children may develop elevated liver functions, most likely due to fat deposits in the liver. Liver function tests (i.e., SGOT and SGPT) that are two or three times above the upper limits of normal require investigation. Blood pressure should be in the 90th percentile and is recommended to be measured at baseline, 3 months and quarterly. Liver function tests may be performed at baseline, 3 months and 6-monthly. Endocrine Monitoring The evaluation of endocrine effects in youngsters can be challenging, therefore frank, discussions with families and youngsters are important. Explain that antipsychotic medications can sometimes cause changes in breasts, sexual interest, or menstrual irregularities. These things should be noted if they occur and reported to the treating clinician. Elevated prolactin levels may be less significant than the development of side effects, and current recommendations include prolactin measurements only when abnormal sexual or reproductive system functioning are present. Nevertheless, studies are needed to confirm that sub-clinically elevated prolactin levels do not adversely affect bone density or pubertal development. Education When discussing treatment options, the entire construct of anticipatory guidance that is so prominent in pediatrics is vital in this arena. Both parents and youngsters should be educated about the potential metabolic effects of antipsychotic medications. Alerting patients and families ahead of time can reduce anxiety, should side effects develop; it can also potentially improve adherence. Intervention Strategies There are limited comparative data that describe the differential efficacy of atypical antipsychotic agents. Moreover, existing evidence in adults and in youth indicate that (with the exception of clozapine) differences in efficacy are less predictable and prominent than differences in adverse effects. Therefore, clinicians should strongly consider specific risk profiles when choosing antipsychotic treatment. Due to the strong association with adverse health outcomes and decreased life expectancy, prevention or amelioration of weight gain and negative metabolic effects is a vital concern when choosing treatment. Initiating therapy with a low metabolic-risk agent may be the safest route, unless there is clear personal or family historical evidence that a specific agent has been particularly beneficial. If that agent turns out not to be effective, a higher metabolic-risk agent is an alternative. When weight and metabolic changes are identified in youngsters receiving an antipsychotic, options to consider include switching to another medication, behavioral and lifestyle interventions, and adjunctive pharmacologic weight loss agents. Although comparative data are lacking, clinicians may want to first attempt a switch of antipsychotic treatment in order to remove the offending agent, rather than adding another medication for weight loss or improvement in metabolic abnormalities. In adults, there are several switch studies that have shown that switching from medium- or high-risk agents to either aripiprazole or ziprasidone results in a significant weight loss and improvement in lipid parameters.27,28 If lifestyle changes are indicated, the first step in changing behavior is to create awareness by providing resources, suggesting specific weight-loss strategies, and setting realistic expectations. (Box 2) Intervention programs based upon diet, exercise, and lifestyle changes are effective in antipsychotic treated adults and in obese youngsters who do not have psychiatric illness.29,30 However, to date, no studies have evaluated their efficacy in youngsters with psychiatric illnesses. While the approaches described in Box 2 are fairly simple, implementation may be a challenge when youngsters are socially, psychologically and psychiatrically impaired. In addition, home environments may be chaotic and not supportive. Clinical experience shows, however, that when families are involved in implementing these programs, a significant number of youngsters lose weight and may maintain the weight loss.
Pharmacologic Interventions Weight management is often an ongoing struggle in patients treated with antipsychotics. Though weight gain tapers off over time, it may only do so after marked weight gain and metabolic abnormalities have occurred. In addition, it is not known if weight loss during the initial phase of treatment can be maintained. A sizeable number of patients cannot achieve weight loss with behavioral interventions alone. On rare occasions, a patient may respond to only one agent and have no therapeutic alternatives. Other patients or their families may not agree to a switch, while others may experience weight gain and metabolic complications even during treatment with lower metabolic-risk agents. For these youngsters, adjunctive pharmacologic interventions to treat these abnormalities may be useful. Two studies have evaluated the effects of metformin in youngsters. Metformin is indicated for the treatment of type 2 diabetes, but it also appears to prevent youngsters from gaining additional weight during treatment with antipsychotics and other psychotropics.31,32 Other drugs that have been considered are sibutramine, orlistat, amantadine, topiramate, and nitazadine. Except for amantadine33 and topiramate,34,35 these agents have been studied in antipsychotic-treated adults or non-psychiatric obese youth, but not in pediatric patients receiving antipsychotic drugs. Sibutramine was shown to be very effective in adults,36 but the FDA denied permission to evaluate it in youngsters, citing a lack of data about the drug-drug interactions with antipsychotics and effects on growing individuals (Correll CU, personal communication). Unfortunately, concurrent use of sibutramine is contraindicated with a selective serotonin reuptake inhibitor (SSRI) or other antidepressants, lithium, or psychostimulants in order to prevent serotonin syndrome, making it very difficult to evaluate it in psychiatric populations.37 Some adult studies and limited pediatric data have suggested that topiramate might affect weight in a positive way, but this potential benefit has to be weighed against the potential for cognitive dulling and word finding difficulties associated with topiramate. Summary Youngsters with psychiatric illness are at increased risk of having metabolic abnormalities. As part of a growing population afflicted with overweight and obesity, they may also develop disease- or treatment-associated weight gain, metabolic, and endocrine abnormalities. Currently, there are no reliable tools to predict which youngsters will experience weight gain or metabolic abnormalities with a specific medication. Nevertheless, adverse effect profiles across antipsychotic agents, particularly weight gain and related metabolic abnormalities, differ predictably in groups of patients. These differences are most likely greater than the differences in efficacy, with the exception of clozapine. Clinicians need to consider the potential risks versus the benefits, especially when initiating treatment. Emerging data suggest that atypical antipsychotics may have higher potential for adverse metabolic effects in youngsters who are treatment-naïve. Youngsters need to be seen more frequently than once per year by a clinician who can monitor and evaluate metabolic changes. Mental health practitioners who prescribe atypical antipsychotic treatments should be an integral part of the monitoring process, targeting the improvement of mental and physical health outcomes. |
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