Children and adolescents with major depression do not benefit from most antidepressant medications, and some of these drugs may do more harm than good. This is the conclusion of a new study published in The Lancet.

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For children and adolescents with major depression, researchers suggest the harms may outweigh the risks when it comes to antidepressant use.

Major depression, or major depressive disorder, is estimated to affect around 2.8 percent of children aged 6-12 years and 5.6 percent of adolescents aged 12-18 years in the United States, according to the study authors.

The condition is normally diagnosed if a child or adolescent experiences depressive symptoms for more than 2 weeks.

These symptoms include mood swings, irritability, changes in eating habits, frequent sadness and crying, low self-esteem, and thoughts of death or suicide.

For children and adolescents with major depression, most clinical guidelines recommend cognitive behavioral therapy (CBT) and other psychological therapies as the first-line treatment.

However, lead study author Dr. Andrea Cipriani, of the University of Oxford in the United Kingdom, and colleagues note that an increasing number of youngsters with major depression are being prescribed antidepressants.

They point to a study published earlier this year that found between 2005-2012, the proportion of children and adolescents (aged 0-19 years) in the U.S. that were taking antidepressants rose from 1.3 percent to 1.6 percent.

Such an increase has occurred despite the U.S. Food and Drug Administration (FDA) warning against antidepressant use for children and adolescents in 2004, after studies found increased suicide risk among young users of the drugs.

"Consequently, the question of whether to use antidepressant drugs for the treatment of major depressive disorder in young people and, if so, which antidepressant would be preferred, remains controversial," say the authors.

Ranking antidepressant effectiveness using four criteria

For their study, the researchers set out to investigate whether the benefits of antidepressant use outweigh the risks for young people with major depression.

The team conducted a systematic review and meta-analysis of all unpublished and published double-blind, randomized controlled trials up to May 2015 that assessed the treatment of major depression among children and adolescents.

The trials included in the analysis assessed the effects of 14 antidepressant medications, and the team ranked the effectiveness of each medication using four criteria:

  • Efficacy - determined by changes in depressive symptoms and response to treatment
  • Tolerability - whether medication use was discontinued due to adverse events
  • Acceptability - whether medication use was discontinued due to any cause
  • Associated serious harms - whether the medication increased suicidal thoughts or events, or other harms.

The researchers accounted for the quality of each study using the Cochrane risk of bias, and they also assessed the overall quality of the evidence from each study using the GRADE framework.

Only fluoxetine showed more benefits than risks

Of the trials included in the analysis, 65 percent of them were funded by drug companies, 29 percent were rated as having high risk of bias, 59 percent had moderate risk of bias, and 12 percent had low bias risk.

In 34 of the trials - including 5,260 participants of average age 9-18 years - the researchers identified only one antidepressant, fluoxetine, for which the benefits outweighed the risks when it came to efficacy and tolerability.

Compared with placebos and seven other antidepressants, nortriptyline was found to have lower efficacy.

The antidepressants imipramine, venlafaxine, and duloxetine fared worst when it came to tolerability, the researchers found; there were many more discontinuations with these drugs than with placebos.

Compared with placebos and five other antidepressant medications, venlafaxine was found to increase the risk of suicidal thoughts and attempts.

These results, say the authors, suggest that the vast majority of antidepressants are ineffective for children and adolescents with major depression, and many of them may be unsafe.

"The balance of risks and benefits of antidepressants for the treatment of major depression does not seem to offer a clear advantage in children and teenagers, with probably only the exception of fluoxetine.

We recommend that children and adolescents taking antidepressants should be monitored closely, regardless of the antidepressant chosen, particularly at the beginning of treatment."

Study co-author Prof. Peng Xie, The First Affiliated Hospital of Chongqing Medical University, China

Lack of reliable data limits accuracy of findings

The researchers note that they were unable to assess the risk of suicidality for all antidepressants because there were insufficient reliable data.

Furthermore, the quality of evidence for primary outcomes in most studies was very low, which the researchers say restricts how the findings may apply to clinical practice.

"Without access to individual-level data it is difficult to get accurate effect estimates and we can't be completely confident about the accuracy of the information contained in published and unpublished trials," says Dr. Cipriani.

In an accompanying editorial, Dr. Jon Jureidini, of the University of Adelaide in Australia, speculates that there may have been more suicidal events reported with antidepressant use if the researchers had access to individual patient data.

Using an example to support his point, he notes that in four trials that compared the antidepressant paroxetine with placebos, only 13 (3 percent) of 413 suicidal events were reported in the group.

"This seems implausible when individual patient-level data reanalysis of just one of those studies found 10 events in only 93 patients given paroxetine (10.8 percent)," he adds.

Dr. Jureidini says that it is possible that antidepressants are more dangerous and less effective for children and adolescents than these inaccurate clinical trials have led us to believe.

"We doctors and researchers are failing to meet our obligation to research participants and to our patients, and we will only succeed if independent researchers such as Cipriani and colleagues are able to analyze individual patient-level data," he explains.

"Claims that appropriate access to such data is incompatible with intellectual property constraints and patient privacy must be strongly resisted."

Read about a study that suggests CBT and antidepressants are equally effective for major depression in adults.