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Are antipsychotics linked to chronic diseases in youth?

A new study determined the effects of first exposure to antipsychotics on weight gain and insulin sensitivity in children and teenagers.

Antipsychotics are medications primarily used to manage symptoms of psychosis such as delusions, hallucinations, and paranoia associated with schizophrenia and bipolar disorder. Antipsychotics are a well-established treatment in adults with serious psychological problems.

Antipsychotics are increasingly being used in children and teenagers for neurodevelopmental, behavioral, and psychiatric disorders. While there is an increase in off-label prescriptions of antipsychotics for children and teenagers, there is not enough understanding of the safety of these drugs in these patients. This is important, as there is emerging evidence that off-label use of antipsychotics has significant adverse effects in youth.

Types of antipsychotics

Antipsychotics are categorized into first-generation (typical antipsychotics) and second-generation (atypical) antipsychotics. Both types of antipsychotics work by blocking receptors in the brain’s dopamine pathways that are key circuits through which dopamine, a neurotransmitter, is spread to different parts of the brain.

Atypical antipsychotics also act on serotonin receptors that are located on nerve cells and mediate the effects of the hormone serotonin.

It is not clear if atypical antipsychotics offer any advantages over the first-generation antipsychotics. Some studies show that second-generation antipsychotics such as olanzapine, risperidone, and aripiprazole that are used as first-line treatment for schizophrenia and bipolar disorder, may be more effective than the first-generation antipsychotics but are also associated with greater side effects.

Do risks outweigh the benefits of antipsychotics in youth?

The increase in the off-label use of antipsychotics in children and teenagers is perhaps because of the lack of alternative treatments. Youth with attention deficit hyperactive disorder (ADHD) or disruptive behavior disorder might benefit from antipsychotics but it is important to consider the risks associated with the use of these drugs. Many studies have shown an association of antipsychotics with serious adverse effects such as weight gain, diabetes, high cholesterol and cardiovascular disease.

Effect of antipsychotics on adiposity and insulin sensitivity

Adiposity and insulin sensitivity are adversely affected by antipsychotic treatment. Adiposity, or the condition of being overweight, is associated with a growing risk of cardiovascular disease and other health issues. Insulin sensitivity describes how sensitive the body is to the effects of insulin. A low insulin sensitivity, also known as insulin resistance, means higher amounts of insulin are needed to lower blood glucose levels and it can lead to various health problems.

Metabolic effects of first exposure to antipsychotics

A team of scientists in the Washington University School of Medicine, Missouri, conducted a randomized clinical trial to determine the metabolic effects of first exposure to antipsychotics in children and adolescents. The study recently published in the JAMA Psychiatry used standard assessment of body composition and insulin sensitivity to evaluate the effects of treatment with antipsychotics.

The trial included 144 participants aged 6 to 18 years who were diagnosed with at least one psychiatric disorder. The participants, who were naïve to antipsychotics, were randomly assigned to receive one of the three commonly used antipsychotics – aripiprazole, olanzapine, or risperidone – for 12 weeks.

The percentage of total body fat, total lean body mass and insulin sensitivity in muscle was measured using direct validated quantification methods at the start of the study, and at 6- and 12 weeks. In addition, abdominal adiposity and adipose and hepatic tissue insulin sensitivity were also measured at the start of the study and at 12 weeks.

Increase in total body fat

During the 12 weeks of treatment with the antipsychotics, the researchers observed an increase in total body fat across all participants compared to the start of the study. The highest increase of 4.1% was observed for olanzapine, followed by 1.6% with aripiprazole and 2.3% with risperidone. Abdominal fat analysis showed an increase in central obesity, with a significantly increased subcutaneous fat for olanzapine compared with risperidone or aripiprazole.

Decrease in insulin sensitivity

The researchers observed a decrease in insulin sensitivity in the combined sample at 12 weeks after treatment with antipsychotics. A 2.3% improvement in insulin sensitivity was observed with risperidone but it declined steeply to 30.2% with aripiprazole and 29.3% with olanzapine.

Improved psychiatric symptoms in youth

The study observed significant improvement in the psychiatric symptoms of the participants. Some adverse effects of the treatment were, however, observed on glucose levels and lipid and hepatic measures. While none of the participants developed diabetes during the study period, nine participants developed above normal fasting glucose levels at the end of the study period.

Treatment with olanzapine produced greater adverse effects

Treatment with olanzapine resulted in greater increase in whole-body adiposity as well as subcutaneous abdominal obesity compared with treatment with risperidone or aripiprazole.  It is important to note that all the adverse effects occurred at low doses of these medications.

The treatment benefits must be weighed against metabolic effects of antipsychotics

While the antipsychotics effectively manage behavioral disorders, the researchers suggest that these benefits must be weighed against the adverse metabolic effects of these drugs in children and adolescents. Increased body fat and reduced insulin sensitivity are factors associated with the development of type 2 diabetes and cardiovascular disease in later life of these patients.

The assessment of adiposity and insulin sensitivity by direct validated quantification methods is the major strength of this study. The main limitation of the study is the short study period of 12 weeks.

Based on the results of the study, the researchers concluded that the decision to use antipsychotics for youths is as important as the decision of selecting the lower-risk medication. All the antipsychotics tested in the study showed adverse effects on adiposity and insulin sensitivity.

Adverse changes in both abdominal adiposity and insulin sensitivity may cause an early onset of type 2 diabetes, cardiovascular disease, and other major illnesses leading to premature morbidity and mortality in these patients. The researchers suggest the need for future studies to explore the clinical indicators of risk associated with the use of antipsychotics.

Written by Preeti Paul, MS Biochemistry

Reference: Ginger E. Nicol et al. Metabolic Effects of Antipsychotics on Adiposity and Insulin Sensitivity in Youths: A Randomized Clinical Trial. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2018.1088

Preeti Paul MSc
Preeti Paul MSc
Preeti has a Master’s degree in Biochemistry. Her career interests include scientific services and clinical research. She is passionate about the dissemination of scientific information to the public. As a medical content writer, Preeti aims to be instrumental in shaping the transmission of scientific advances to the general public so that they can make informed decisions. In her free time, she likes to travel, cook and advocate toxin-free living.


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