James T. Cullinan, DO
Assistant Professor of Psychiatry
Department of Psychiatry, Division of Child and Adolescent Psychiatry
The University of Alabama at Birmingham
Birmingham, Alabama

In accordance with the Accreditation Council for Continuing Medical Education Standards for Commercial Support, Dr. Cullinan discloses research support from Pfizer, Inc., Otsuka American Pharmaceuticals and UCB, Inc.

The University of Alabama School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The University of Alabama School of Medicine designates this educational activity for a maximum of 0.25 AMA PRA Category 1 credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The boards of nursing in many states, including Alabama, recognize Category 1 continuing medical education courses as acceptable activities for the renewal of license to practice nursing.

The Food and Drug Administration (FDA) mandated in 2004 that antidepressants display a black box warning indicating they are associated with an increased risk of suicidal thinking, feeling, and behavior in children and adolescents. The black box also states if the particular drug is approved for pediatric use. The FDA based its original warning on a meta-analysis of 24 short-term placebo-controlled trials that found the risk of suicidal ideation, behaviors, or a suicide attempt was twice as high (4% vs 2%) among children and adolescents receiving antidepressant drugs than among those receiving placebo.

In 2005 additional labeling included further warnings, an appeal to families and caregivers to closely observe the patient and communicate with the prescribing physician, and consumer-friendly medication guides to help caregivers monitor patients.

In the year after the FDA instituted its warning, overall prescriptions for antidepressants decreased almost 10%, new prescriptions declined approximately 20%, and selective serotonin reuptake inhibitor (SSRI) and selective norepinephrine reuptake inhibitor prescriptions decreased by 12%. In the same year, adolescent suicides increased 18%.

In an effort to disentangle effects of treatment from those of illness, the FDA completed a comprehensive meta-analysis of 295 individual antidepressant trials conducted during the past 2 decades. The analysis included trials of bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, and venlafaxine. The FDA’s Psychopharmacologic Drugs Advisory Committee determined the trend across age groups toward an association between antidepressants and suicidality was convincing enough to retain and update the black box warning, and in May 2007 the FDA expanded the cautionary language to incorporate information about the risks and benefits of antidepressants. It warns of an increased risk of suicidality in young adults aged 18 to 24 years during initial treatment but includes the statement that depression and other serious psychiatric disorders are themselves the most important causes of suicide.

Such a nuanced warning leaves clinicians, families, and patients in a quandary about treatment. UAB child and adolescent psychiatrist James T. Cullinan, DO, generally agrees with the FDA’s concerns and actions, but voices reservations. “Clinicians must carefully weigh the risks and benefits of pediatric antidepressant use. My greatest concern is these warnings may further tip the balance toward excessive alarm among parents and physicians and result in children not being treated for depressive disorders, which are serious diseases associated with high rates of comorbidity, poor psychosocial outcomes, and increased risks for substance abuse and suicide,” says Cullinan, who notes up to 15% of all people with depression eventually kill themselves.

The National Institute of Mental Health (NIMH) reports depression affects up to 2.5% of children and 8% of adolescents in the United States. “Depression in children and teenagers can be difficult to diagnose,” Cullinan says. “Depressive disorders in pediatric populations are often unrecognized because symptoms can be misinterpreted as normal moodiness associated with growing up. Symptoms can overlap with nonaffective conditions, such as separation anxiety, attention deficit disorders, anxiety disorders, learning problems, eating disorders, and substance abuse.” Symptoms that can confound the diagnosis of depression include impaired self-esteem, concentration, and sleeping patterns; dysphoria; appetite problems; feeling overwhelmed; and suicidal thoughts.

“Only clinicians with expertise in pediatric depression should diagnose the disorder. A careful history of symptom development is key to an accurate diagnosis. Physicians also should consider family history of mental illness and rule out effects of drugs or other medical conditions,” he says.

Overall, adolescent suicide is rare, but suicidal thinking or attempts are relatively common. Of teenagers aged 15 to 19 years, 19% make a suicide attempt. Among youth receiving care for depression, 35% to 50% will make a suicide attempt (Am J Psychiatry. 2006;163:1898-1904). The majority of youths who commit suicide are not taking antidepressants at the time of their death.

Before the introduction of SSRIs, pediatric patients had few pharmaceutical options. “Earlier medications such as tricyclic antidepressants were less frequently prescribed for children or adolescents because of intolerable side effects. Newer drugs are easier to use, have few problematic side effects, and do not require blood tests or complicated titrations.”

Fluoxetine, the only SSRI with FDA approval for use in children with depression, is currently the fifth most prescribed pediatric antidepressant.

Scientists have proposed several explanations for antidepressant-associated suicidal behaviors. “Suicidal thinking is one of a cluster of depressive symptoms that also include low energy, low mood, and poor sleeping,” Cullinan says. “The first weeks of treatment and the period after dose increases are when suicidal behavior most often occurs. Certain symptoms may improve more rapidly than others, and patients’ energy levels might increase faster than their depressed mood lifts, making them more likely to act on preexisting suicidal impulses.”

The extent to which antidepressants may cause suicidality in youth is undetermined, and mixed results of current research confound the issue. A 2006 study using national Medicaid files found an increased risk of suicide attempts among children and adolescents using antidepressants, while a large observational study from the same year shows risk of a suicide attempt decreases after patients begin drug therapy (Arch Gen Psychiatry. 2006;63:865-872) and (Am J Psychiatry. 2006;163:41-47).

Another 2006 study links a decrease in the adolescent suicide rate with increased antidepressant use and suggests the medications may protect against completed suicide in children and young adolescents (Am J Psychiatry. 2006;163:1898-1904). A 2007 meta-analysis concludes the benefits of antidepressants for children and teenagers may outweigh the risks. Researchers found beneficial effects to be strongest in nonobsessive-compulsive anxiety disorders, intermediate in OCD, and more modest in major depressive disorder (JAMA. 2007;297:1683-1696).

New NIMH research may help clarify the issue. Five multiyear projects are being conducted to elucidate the connection between SSRI use and suicidal thinking and behavior. These include investigations of how SSRIs may induce an activation syndrome in pediatric patients with OCD; the impact of FDA actions on SSRI use and rates of suicidality; and development of a computer tool to screen for suicidality associated with antidepressant use. In addition, three new NIMH studies aim to determine optimal treatments to reduce depression and suicidal behavior.

Although the public and the FDA have focused attention on the safety of antidepressants in children, efficacy also is controversial. Fluoxetine is the only drug to show statistically significant benefit. Showing efficacy in treatment of pediatric depression can be difficult, Cullinan says. “Many other antidepressants may be effective, but most of them have shown inconsistent benefit in pediatric trials. Participants selected for studies of antidepressants may not match populations seen in practice; results of those studies cannot be extrapolated to all patients; and trials are sometimes brief, so patients may get inadequate doses for too short a time.”

When considering antidepressant use in children or adolescents, the risk of suicidal thinking and behavior must be balanced with clinical need. “If, after thorough evaluation, depression is diagnosed, a medication might be indicated as part of the treatment plan,” Cullinan says. “Once medication is prescribed, it is crucial that physicians carefully and frequently re-evaluate the child in face-to-face meetings, especially in the early treatment stage [1 to 2 months].”

“Although the FDA warning hopefully will increase awareness of the critical need for careful diagnosis and close monitoring, physicians and parents should understand that depression itself can cause suicidal thinking, behaviors, and completed suicides, and these symptom patterns are not exclusively side effects of medication,” Cullinan says. “The worst treatment would be no treatment at all.”

For more information:

Dr. James Cullinan
1-800-UAB-MIST
mist@uabmc.edu

To take the test click here!