Children are known for their active imaginations, but it’s extremely rare for them to have true psychotic symptoms. A study co-led by Joseph Gonzalez-Heydrich, MD, a psychiatrist at Boston Children’s Hospital, has now found a high frequency of copy number variants (CNVs) in children and adolescents with early onset psychosis (EOP)—psychotic symptoms appearing before age 18 years. The researchers are urging that any child with psychotic symptoms should undergo genetic testing, as is already recommended for individuals with autism spectrum disorder (ASD).

Co-study lead Catherine Brownstein, MPH, PhD, scientific director of the Manton Center for Orphan Disease Research at Boston Children’s and a member of the Division of Genetics and Genomics, oversaw the genetic testing of more than 100 children with EOP, for the reported study. She noted that finding a CNV can help parents connect with other families for reassurance and support.

Also, once a CNV is found, scientists can study what the lost or duplicated genes do. This could lead to a better understanding of the origins of early psychosis and possibly to better antipsychotic drugs, which have changed little since the 1950s. “We don’t have medications tailored to CNVs yet,” Brownstein said. “But when parents get together, they can organize and identify research devoted to their particular CNV. We can study their children as a group and identify effective treatments a lot faster.”

Gonzalez-Heydrich, Brownstein, and colleagues published their study in a paper in American Journal of Psychiatry, titled, “Similar Rates of Deleterious Copy Number Variants in Early-Onset Psychosis and Autism Spectrum Disorder,” in which they concluded, “… the high frequency of CNVs in our EOP cohort suggests that routine screening for CNVs should be made available to EOP patients and could have important implications for genetic counseling and patient management … Overall, genetic screening in EOP has the potential to bring us one step closer to true precision medicine in pediatric psychiatry.”

A six-year-old boy began hearing voices coming from the walls and the school intercom telling him to hurt himself and others. He saw ghosts, aliens in trees, and colored footprints. Gonzalez-Heydrich put him on antipsychotic medications and the frightening hallucinations stopped. Another child, at the age of four years, had hallucinations of monsters, a big black wolf, spiders, and a man with blood on his face. Through chromosomal array testing, both children were found to have CNVs, which are deletions or duplications of chunks of their DNA.

CNVs are strongly associated with neurodevelopmental and psychotic disorders, the authors explained, and early-onset psychosis, where symptoms appear before 18 years of age, is thought to be more strongly influenced by genetic factors than adult-onset psychotic disorders. While “functional outcomes are highly variable in youths with EOP, and CNV status has been shown to influence these outcomes,” the team continued, “ … the prevalence and effect of CNVs in EOP is unclear.” They further suggested, “Although genomic information could help to disentangle the clinical heterogeneity in EOP, the genetic architecture of EOP is largely unknown.”

For their study, through the Early Psychosis Investigation Center (EPICenter) at Boston Children’s, Gonzalez-Heydrich and his colleagues David Glahn, PhD, and Brownstein, genetically tested 137 children and adolescents with EOP to investigate the prevalence and effects of CNVs, compared with 5,540 individuals with ASD, and another 16,504 control subjects. “Specifically, the frequency of 47 recurrent CNVs previously associated with neurodevelopmental and neuropsychiatric illnesses in each cohort were compared,” the team stated.

More than 70% of the EOP children in the study had begun experiencing psychosis before the age of 13. Twenty-eight percent met formal criteria for schizophrenia, having persistent and unrelenting symptoms. All the participants underwent systematic testing for CNVs. A surprising 40% tested positive. The screening results showed that CNVs were as common among individuals with EOP as they are in children with autism, who are often screened for CNVs in the clinic. In many cases, the CNVs identified had also been linked to other psychiatric and neurodevelopmental disorders.

“Our findings make a strong case for chromosomal microarray testing in any child or adolescent diagnosed with psychosis,” said Brownstein, who co-led the study with Elise Douard at the Université de Montréal. “Testing often brings closure for families, and could help advance research.” The authors further wrote, “Given the success of genetic screening in ASD, our findings suggest that all children and adolescents with a psychosis diagnosis could substantially benefit from chromosomal microarray testing, with the potential for further testing contingent upon family history and/or clinical features.”

Families are often relieved to learn that their child’s psychotic symptoms have a biological component. Their child’s psychosis may have been misdiagnosed, explained away as a normal developmental phase, attributed to stresses like being bullied, or even blamed on bad parenting. “Many parents feel like they are put under the microscope, or are even accused of triggering their child’s symptoms,” says Gonzalez-Heydrich. “It parallels what happened with autism a generation ago.”

In other cases, psychosis may be missed because the child also has autism or a different developmental disorder. Just over a third of children in the study had a diagnosis of autism spectrum disorder, 12% had intellectual disability, and 18% had a history of seizures.

Clinicians may sometimes be reluctant to stigmatize a child by diagnosing them with psychosis, preferring to watch and wait. But, the researchers suggest, finding a CNV might justify a trial of antipsychotic medications to see if they help. “The longer psychosis goes untreated, the harder it is to treat later on,” said Glahn. “If we can treat it earlier and appropriately, the child will likely do better over their lifetime.” As the authors commented, “Universal genetic screening could help disentangle the clinical heterogeneity among youths with EOP, potentially leading to specific treatment regimens.” The team also pointed out that relatively high prevalence risk alleles could also represent “… promising targets for biological research aimed at developing animal and cellular models to identify novel disease mechanisms and drug targets for psychotic disorders.”

Many children have behaviors that may seem like psychosis, for example, having an imaginary friend. But true psychosis is distressing to children and outside their control, noted Glahn and Gonzalez-Heydrich. “It’s not simply the child thinking someone’s talking about them because they’re socially anxious,” pointed out Gonzalez-Heydrich. “It’s multiple voices criticizing them, scaring them, telling them to do bad things. Or feeling that strangers are staring at them, planning to do them harm.”

In some children, psychotic symptoms come and go. Psychosis can appear when a child is under stress, angry, very depressed, or having mood swings. But in children with true schizophrenia, symptoms are persistent and extreme. This is very rare in children under 10 years of age, but becomes less rare in adolescence and early adulthood. For perspective, schizophrenia affects just 1–2% of the general population, including adults.

The earliest signs of psychotic illness may be general. A child may become withdrawn. Their day-to-day functioning may decline, sometimes dramatically, interfering with school and relationships. Or they may have outbursts where they hadn’t before. Later, hallucinations and paranoia may take hold, causing the child to see and hear things that aren’t there, often things that feel threatening.

Besides encouraging treatment, finding a CNV in a child with psychosis allows other family members to be tested to see if they are at risk. Some CNVs can also be linked with medical complications like seizures, heart problems, or weakened blood vessels that can be watched and treated. Family members found to have CNVs may also be at risk for such medical problems, even if they don’t have behavioral symptoms. “… children and adolescents with EOP who carry recurrent CNVs associated with serious nonpsychiatric medical conditions (e.g., cardiovascular abnormalities in 22q11.2 deletion syndrome or the high incidence of hypotonia and epilepsy in 15q11.2 duplication carriers) could be more carefully monitored,” the scientists commented.

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