Antidepressants and Youths: What we’ve learned in the decade since the black box

Ten years ago, the Food and Drug Administration required that all antidepressants carry a severe black box warning to alert prescribers to the possibility that these medications could cause worsening suicidal thoughts and behavior. A decade later, this issue had faded from the public eye and the media headlines. Nevertheless, research into their use has continued, and antidepressants continue to be prescribed. Have things changed since all the attention in the past? The results may be surprising.

Although there are undoubtedly different views, here is my summary of the five key points with direct implications for pediatricians:

1. The risk of suicide due to antidepressants was overstated. Subsequent analyses from additional clinical trials comparing suicidal thoughts or behavior between youths taking antidepressants versus placebo have increasingly struggled to find that "signal" related to active drug. Perhaps more importantly, several other studies that have examined actual suicides and/or suicide attempts from large databases have not shown links to the taking of antidepressants and, if anything, have suggested that untreated depression poses a greater risk (BMJ 2014;348:g3596). It is worth repeating that there still has never been an actual suicide in any of the antidepressant trials.

2. The efficacy of antidepressants also was overstated. As people began to examine more closely the issue of suicidal behavior and antidepressants, it became evident that there was much more data on this than was obvious from published studies. Many more trials of depression and antidepressants were performed, usually funded by pharmaceutical companies, and many of these trials did not show that antidepressants were superior to placebo (N. Engl. J. Med. 2008;358:252-60). As opposed to the positive trials, however, the negative ones tended not to be published or featured. Overall, it seems that about 60% of depressed children and adolescents respond to antidepressant medication, compared with 50% who respond to placebo.

3. The prescribing of antidepressants is making a comeback. After the 2004 warnings, the number of antidepressant prescriptions dropped. Since around 2008, however, the rate of antidepressant prescribing has increased again, although not at 2004 levels, according to some studies.

4. Antidepressants don’t work by fixing a serotonin "chemical imbalance." Although it is true that antidepressants result in more serotonin being available in brain synapses acutely, depression is not caused by a simple serotonin deficit. Medications likely work by changing the expression of certain genes that relate to how strongly particular brain pathways are connected. This process may explain why antidepressants take time to be effective.

5. Antidepressants actually work better for youths with anxiety rather than depression. More promising results with antidepressants have been found for children with anxiety disorder and obsessive-compulsive disorder (N. Engl. J. Med. 2008;359:2753-66). Although cognitive-behavior therapy remains the recommended first-line intervention for children with anxiety disorders, antidepressants have been shown to be effective both alone and in combination with cognitive-behavior therapy.

There is still much to learn. Children and adolescents who are extremely irritable, unmotivated, and at times suicidal are a diverse group of people whose difficulties can arise from many factors that deserve investigation. When it comes to antidepressants, it appears that both the amount of risk and the amount of benefit associated with this class of medications may be less than what was believed a decade ago.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Follow him on Twitter @pedipsych. Dr. Rettew said he had no financial disclosures relevant to this article.

Ten years ago, the Food and Drug Administration required that all antidepressants carry a severe black box warning to alert prescribers to the possibility that these medications could cause worsening suicidal thoughts and behavior. A decade later, this issue had faded from the public eye and the media headlines. Nevertheless, research into their use has continued, and antidepressants continue to be prescribed. Have things changed since all the attention in the past? The results may be surprising.

Although there are undoubtedly different views, here is my summary of the five key points with direct implications for pediatricians:

1. The risk of suicide due to antidepressants was overstated. Subsequent analyses from additional clinical trials comparing suicidal thoughts or behavior between youths taking antidepressants versus placebo have increasingly struggled to find that "signal" related to active drug. Perhaps more importantly, several other studies that have examined actual suicides and/or suicide attempts from large databases have not shown links to the taking of antidepressants and, if anything, have suggested that untreated depression poses a greater risk (BMJ 2014;348:g3596). It is worth repeating that there still has never been an actual suicide in any of the antidepressant trials.

2. The efficacy of antidepressants also was overstated. As people began to examine more closely the issue of suicidal behavior and antidepressants, it became evident that there was much more data on this than was obvious from published studies. Many more trials of depression and antidepressants were performed, usually funded by pharmaceutical companies, and many of these trials did not show that antidepressants were superior to placebo (N. Engl. J. Med. 2008;358:252-60). As opposed to the positive trials, however, the negative ones tended not to be published or featured. Overall, it seems that about 60% of depressed children and adolescents respond to antidepressant medication, compared with 50% who respond to placebo.

3. The prescribing of antidepressants is making a comeback. After the 2004 warnings, the number of antidepressant prescriptions dropped. Since around 2008, however, the rate of antidepressant prescribing has increased again, although not at 2004 levels, according to some studies.

4. Antidepressants don’t work by fixing a serotonin "chemical imbalance." Although it is true that antidepressants result in more serotonin being available in brain synapses acutely, depression is not caused by a simple serotonin deficit. Medications likely work by changing the expression of certain genes that relate to how strongly particular brain pathways are connected. This process may explain why antidepressants take time to be effective.

5. Antidepressants actually work better for youths with anxiety rather than depression. More promising results with antidepressants have been found for children with anxiety disorder and obsessive-compulsive disorder (N. Engl. J. Med. 2008;359:2753-66). Although cognitive-behavior therapy remains the recommended first-line intervention for children with anxiety disorders, antidepressants have been shown to be effective both alone and in combination with cognitive-behavior therapy.

There is still much to learn. Children and adolescents who are extremely irritable, unmotivated, and at times suicidal are a diverse group of people whose difficulties can arise from many factors that deserve investigation. When it comes to antidepressants, it appears that both the amount of risk and the amount of benefit associated with this class of medications may be less than what was believed a decade ago.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Follow him on Twitter @pedipsych. Dr. Rettew said he had no financial disclosures relevant to this article.

Ten years ago, the Food and Drug Administration required that all antidepressants carry a severe black box warning to alert prescribers to the possibility that these medications could cause worsening suicidal thoughts and behavior. A decade later, this issue had faded from the public eye and the media headlines. Nevertheless, research into their use has continued, and antidepressants continue to be prescribed. Have things changed since all the attention in the past? The results may be surprising.

Although there are undoubtedly different views, here is my summary of the five key points with direct implications for pediatricians:

1. The risk of suicide due to antidepressants was overstated. Subsequent analyses from additional clinical trials comparing suicidal thoughts or behavior between youths taking antidepressants versus placebo have increasingly struggled to find that "signal" related to active drug. Perhaps more importantly, several other studies that have examined actual suicides and/or suicide attempts from large databases have not shown links to the taking of antidepressants and, if anything, have suggested that untreated depression poses a greater risk (BMJ 2014;348:g3596). It is worth repeating that there still has never been an actual suicide in any of the antidepressant trials.

2. The efficacy of antidepressants also was overstated. As people began to examine more closely the issue of suicidal behavior and antidepressants, it became evident that there was much more data on this than was obvious from published studies. Many more trials of depression and antidepressants were performed, usually funded by pharmaceutical companies, and many of these trials did not show that antidepressants were superior to placebo (N. Engl. J. Med. 2008;358:252-60). As opposed to the positive trials, however, the negative ones tended not to be published or featured. Overall, it seems that about 60% of depressed children and adolescents respond to antidepressant medication, compared with 50% who respond to placebo.

3. The prescribing of antidepressants is making a comeback. After the 2004 warnings, the number of antidepressant prescriptions dropped. Since around 2008, however, the rate of antidepressant prescribing has increased again, although not at 2004 levels, according to some studies.

4. Antidepressants don’t work by fixing a serotonin "chemical imbalance." Although it is true that antidepressants result in more serotonin being available in brain synapses acutely, depression is not caused by a simple serotonin deficit. Medications likely work by changing the expression of certain genes that relate to how strongly particular brain pathways are connected. This process may explain why antidepressants take time to be effective.

5. Antidepressants actually work better for youths with anxiety rather than depression. More promising results with antidepressants have been found for children with anxiety disorder and obsessive-compulsive disorder (N. Engl. J. Med. 2008;359:2753-66). Although cognitive-behavior therapy remains the recommended first-line intervention for children with anxiety disorders, antidepressants have been shown to be effective both alone and in combination with cognitive-behavior therapy.

There is still much to learn. Children and adolescents who are extremely irritable, unmotivated, and at times suicidal are a diverse group of people whose difficulties can arise from many factors that deserve investigation. When it comes to antidepressants, it appears that both the amount of risk and the amount of benefit associated with this class of medications may be less than what was believed a decade ago.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Follow him on Twitter @pedipsych. Dr. Rettew said he had no financial disclosures relevant to this article.