The US Food and Drug Administration has warned that antidepressants may be linked with suicidal thoughts and behaviors among youth since 2003, leading to a black box warning for minors in 2005 and an expansion to young adults in 2007.

The black box, or boxed, warning refers to a prominent warning encased in a bold black border in the labeling or pamphlet of some medications. It’s meant to raise awareness of certain risks of taking the drug and to increase physician monitoring of suicidality.

But new research has found boxed warnings on antidepressants may have had unintended negative consequences for pediatric health care and suicidality — including reductions in mental health care and increases in psychotropic drug poisonings and suicide deaths, according to the systematic review published Monday in the journal Health Affairs. (Psychotropic drugs or other substances influence how the brain functions and cause changes in mood, awareness, thoughts, feelings or behavior.)

“Our goal was to assess the intended and unintended outcomes of the youth antidepressant warnings by conducting a systematic review of the most credible evidence in the field,” said lead study author Dr. Stephen Soumerai, professor of population medicine at the Harvard Pilgrim Health Care Institute and Harvard Medical School in Massachusetts, in a news release. “We screened all available research reports on the warnings, focusing on those that met rigorous research design criteria and synthesized the most trustworthy data available.”

The 11 reports on which the findings are based included previous studies that measured immediate changes in outcome trends following the 2003 FDA advisory or the 2005 boxed warnings.

Some found the surveillance of suicidality lacking. Following the FDA advisory and warning, doctors monitored fewer than 5% of pediatric patients in accordance with the FDA’s recommendations for scheduled contact with patients — a rate similar to that of the pre-warning period, the authors found. None of the studies noted improvements in mental health care or declines in suicide attempts or deaths after the warnings were implemented.

To the contrary, four studies totaling more than 12 million patients found significant declines in doctor visits for depression symptoms or diagnoses. While an increase in antidepressant use occurred before the FDA advisory, there were abrupt and sustained declines in use — ranging from 20% to 50% — after the warnings.

Three studies reported increases in psychotropic drug poisonings, which suggest suicide attempts, and in suicide deaths among children. The effects of the warnings also spilled over to young adults ages 18 to 24.

“The sudden, simultaneous, and sweeping effects of these warnings — the reduction in depression treatment and increase in suicide — are documented across 14 years of strong research,” Soumerai said. “The consistency in observed harms and absence of observed benefits after the Black-Box Warnings indicate this is not a coincidence.

“We recommend that the FDA consider incorporating the Black-Box Warnings into the list of routine warnings that pose fewer health risks, or potentially removing the warnings altogether.”

In response to a request for comment, an FDA spokesperson said via email that in general, the agency does not comment on specific studies.

“The evaluation of product safety is an ongoing and continuous process, and we routinely consider new data, including published literature, as part of our postmarketing pharmacovigilance,” the spokesperson added.

The new study doesn’t show that antidepressants or boxed warnings directly cause suicidality, said Dr. Lisa R. Fortuna, chair of the Council on Children, Adolescents and Their Families at the American Psychiatric Association, via email. Fortuna wasn’t involved in the study.

Understanding the findings

In the United States, depression is a leading cause of suicide, and suicide is the second-leading cause of death among 10- to 14-year-olds and the third-leading cause of death among 15- to 24-year-olds, according to the National Institute of Mental Health.

Since the boxed warnings went into effect, psychiatric best practices have been to treat moderate to severe depression in adolescents, following up within two weeks after beginning antidepressant use and similarly after any dose increase, said Fortuna, professor and chair of the department of psychiatry and neuroscience at the University of California, Riverside. Families are to be informed of the warnings and counseled on the relative risks of untreated depression over the risks of antidepressants.

However, “the study convincingly suggests that the Black Box warning may have made at least some providers and families anxious about treating adolescents with antidepressants,” Fortuna said. “The FDA warnings were intended to increase physician monitoring of suicidal thoughts and behavior, so it was surprising that this does not seem to be the case.”

The lack of monitoring may also have to do with overwhelmed clinical practices, Fortuna said. Many youth psychiatrists have noted more referrals of depressed youth from pediatricians due to concerns about prescribing antidepressants, but there aren’t enough providers to see all the youth who need that care.

It’s important to note that increases in suicide rates could be due to factors other than the boxed warnings, Fortuna said, as “we are amid a mental health crisis in the United States, and there has been a lot of research on increasing mental illness and suicidality over the last decade and heightening during the pandemic.”

Accounting for all potential causes in one study is difficult, but the authors tried to take many into account, so “the findings are at least worth considering seriously,” Fortuna said.

Additionally, the findings on abrupt decreases in antidepressant use are technically based on declines in the dispensing of antidepressants, said Dr. Kao-Ping Chua, associate professor of pediatrics at the Susan B. Meister Child Health Evaluation and Research Center at the University of Michigan Medical School. Chua wasn’t involved in the research.

But it’s unclear “whether this represents inappropriate withholding of antidepressants to young people with severe depression versus a cessation of antidepressant therapy in young people who never or no longer needed to be on these medications,” Chua added via email.

Another limitation is that the review focused on the short- to medium-term effects of a warning issued 20 years ago, Chua said.

“We do not know whether these effects have persisted,” he added. “There is reason to suspect they have not. For example, our previous study showed that there was a sharp rise in antidepressant dispensing to female adolescents and young adults during the COVID-19 pandemic — a rise that occurred despite the FDA black box warning being in place.”

Treating your child’s depression

If you notice drastic changes in your children’s behavior or mood — such as in their sleep, social life, attitude, school performance, ability to concentrate or interest in activities — they may be struggling with depression. Addressing it can be a complex process fraught with concerns about how to treat symptoms without putting kids at risk of further harm.

“It is true that the decision on whether to start antidepressant therapy should not be made lightly, but frankly, that is true for any long-term medication,” Chua said. “All medications have potential benefits and potential side effects. The question is whether the former are likely to outweigh the latter.”

Treatment options, including different therapies, should be discussed with a clinician who takes the time to discuss the pros and cons with young patients and their families so a fully informed decision can be made, Chua said.

“No questions should be off limits,” Fortuna said. “I also believe that the FDA warnings’ intentions to increase physician monitoring of suicidal thoughts and behaviors are good.”

Young people with depression should “be fully assessed and monitored closely whether they have started an antidepressant or not, but especially if prescribed a medication,” she added.

Potential side effects typically resolve within a couple of weeks or so, and if they don’t, a provider may recommend a different medication. Every young person differs in the level of risk, needs and circumstances, Fortuna said, and antidepressants can be lifesaving.