Studies Suggest Spravato Would Benefit Younger People With Treatment-Resistant Depression

Approved in 2019, Spravato (esketamine) nasal spray is on its way to becoming a blockbuster medication for treatment resistant depression (TRD).

But this fast-acting antidepressant is so far approved only for adults with TRD and major depressive disorder in conjunction with a slower-acting antidepressant.

Amid a surge of childhood depression incidence since the COVID-19 pandemic, advocates have urged that Spravato be approved also for younger age groups. In 2021, as many as 20.1% of U.S. adolescents (12-17) had at least one major depressive episode, according to the National Institute of Mental Health. Depression-related suicide is a leading factor in juvenile mortality.

Spravato is a derivative of the anesthetic ketamine, which has long been used off label for the treatment of depression.

Research on ketamine and Spravato in pediatrics is relatively sparse, although it does exist and findings have been positive. “These provide compelling evidence on the efficacy of [Spravato] and ketamine in treating adolescents with TRD and [major depressive disorder, MDD],” wrote Simone Pardossi, MD, lead author of a review of four recent studies on ketamine and Spravato published in the journal Children. Pardossi is with the Department of Molecular Medicine at University of Siena School of Medicine, in Siena, Italy.

However, Janssen, a division of Johnson & Johnson, the maker of Spravato, declined to comment on whether it intends to seek a pediatric indication for the nasal spray. The drug is available off label for treatment of pediatric and young adults.

TRD, generally defined as failed efficacy of two or more antidepressants during a single bout of depression, occurs in 30% to 40% of adolescents with MDD. In adults, the incidence reaches up to 28%).

Partly at issue is how Spravato and ketamine will affect young, developing minds. There is evidence that ketamine can alter the brain’s ability to form and organize synaptic connections.

Evidence also suggests that early exposure to psychotropic substances may elevate the risk for developing psychiatric disorders later in life.

Pediatric patients are also more susceptible to becoming addicted to ketamine and forming substance abuse disorders.

Nevertheless, limited pediatric studies of ketamine and Spravato have shown significant improvements in depression scores.

Investigators argue there is an unmet need for effective treatments in TRD that may make the risk profile of ketamine and Spravato acceptable. “Adolescents suffering from TRD face persistent depressive symptoms and an elevated risk of suicide, which is the leading cause of death among this age group,” Pardossi and his colleagues wrote.

“Notably, [a 2018 Spravato trial (N = 147) of adolescents] underscores the potential of [Spravato] as a viable adjunctive treatment in TRD in adolescents.” In that trial, Spravato outperformed the standard of care in improving the severity of depression symptoms, as measured by the Children’s Depression Rating Scale-Revised (CDRS-R).

However, Pardossi and his co-investigators noted the value of conducting further studies of Spravato in adolescent populations, “to fully understand the long-term effects and optimal usage in this population.”