Treatment Of Pediatric Depression Research Articles

Restrictions on pharmaceutical detailing reduced off-label prescribing of antidepressants and antipsychotics in children.

The treatment of pediatric depression is controversial because it includes substantial prescribing of drugs for uses that have not been approved by the Food and Drug Administration ("off label") and are not evidence based. Some academic medical centers (AMCs) restrict "detailing" by pharmaceutical sales representatives, or the promoting of drugs directly to physicians via sales calls, to reduce the effect of such marketing on physician prescribing. With data from thirty-one geographically diverse AMCs and their affiliated hospitals, we used a difference-in-differences model to estimate the effect of anti-detailing policies on off-label prescribing of antidepressants and antipsychotics by pediatricians and by child and adolescent psychiatrists in the period January 2006-June 2009. We found that after the introduction of such policies, prescriptions for off-label use of promoted drugs fell by 11 percent, consistent with the ongoing presence of off-label marketing to physicians. Prescriptions for on-label use of promoted drugs fell by 34 percent after the adoption of the policies. Conversely, prescriptions for on-label use of nonpromoted drugs rose by 14 percent, and those for off-label use of nonpromoted drugs rose by 35 percent. These results suggest that pharmaceutical sales representatives promoted drugs not approved for pediatric use and that policies that restrict detailing by those representatives reduced such off-label prescribing.

Antidepressants for children with depression.

The Forum about treating depressed children presented in the previous issue of the journal[1],[2] highlighted several important issues about this controversial topic. Depression in children is a devastating disorder that effects psychosocial development and has long-term negative outcomes for both the patients and their families.[3]-[5] It has a relatively high prevalence of 1 to 2% in children and 3 to 8% in adolescents[3], but there are few randomized controlled trials on the efficacy of pharmacotherapy and other treatments for the disorder.[3]-[9] After the FDA's ‘black box’ warning about the potential suicide risk of antidepressant use in children in 2004, the diagnosis of pediatric depression in the United States decreased from 5 per 1000 managed care enrollees to 3 per 1000 and the prescription of antidepressants among treatment-naive patients with depression who were 5 to 21 years of age decreased by approximately 50%.[6] These changes following the FDA warning suggest that many children with depression were not being treated with appropriate medication. This hypothesis is supported by the increase in the suicide rates of children and adolescents – by 14% in the United States[10] and 25% in Canada[6]—in the years following the FDA warning compared to increasing antidepressant prescription use and a decline in suicide rates among children and youth in the years prior to the warning.[6],[7] The results of several reviews about the association between the treatment of pediatric depression with antidepressants and suicidality have questioned the appropriateness of the FDA warning.[5]-[11] Ecological studies have reported a beneficial effect of antidepressant prescription in children and adolescents. In the United States, suicide rates among children and adolescents decreased from 4.4 per 100,000 to 2.8 per 100,000 between 1999 and 2003, a period during which there was a substantial increase in the rates of prescription of selective serotonin reuptake inhibitor (SSRI) antidepressants for pediatric depression.[6] The Treatment for Adolescents with Depression Study (TADS) found that adolescents with major depressive disorder (MDD) show significant decreases in suicidality in all treatment arms but no significant difference in between those treated with fluoxetine and those treated with CBT.[12] More recent studies also indicate that antidepressants are modestly effective for the treatment of pediatric MDD and that the benefits outweigh the risks of suicidalilty.[11] Finally, the FDA's warning applied to all antidepressants, but it appears that the relationship between antidepressant use and suicidality in children and adolescents varies for the different types of antidepressants.[4] Despite the limited number of randomized controlled trials of pharmacotherapy for children with depressive disorders and the inconsistency of the results,[5] several studies found that SSRIs were significantly superior to placebo.[5],[6],[9]-[11] But some studies report antidepressants of limited use in children with depression.[9] Psychotherapy, especially CBT, and manipulation of the psychosocial context (including treatment of parental psychopathology) is considered effective for most children with mild or moderate depression,[7],[10] but usually needs to be augmented with antidepressants in those with severe depression.[9] Based on scientific reviews and expert consensus statements, several practice guidelines recommend using fluoxetine or escitalopram – both of which are approved by the FDA – as the first-line pharmacological treatment for children and adolescents with MDD if medication is indicated.[5]-[11] With appropriate monitoring for suicidality and other potential adverse events, patients with severe forms of pediatric MDD or with less severe MDD that does not respond to psychosocial interventions alone will often benefit from combined psychosocial and psychopharmacological interventions.

PSYCHOTROPIC MEDICATIONS: AN UPDATE FOR SCHOOL PSYCHOLOGISTS

This article provides an overview of medications used frequently in the treatment of pediatric depression, anxiety, and bipolar disorder. The need for a collaborative relationship between the prescribing physician, school personnel, and the family is outlined. School psychologists can play crucial roles by providing the physician with information at the time of referral, developing school‐based psychosocial interventions that augment pharmacological treatment, completing periodic evaluations to assist in symptom monitoring, and alerting the family and physician to any adverse side effects.

Long-term Treatment of Pediatric Depression With Psychotherapies

Major depressive disorder in children and adolescents is associated with significant morbidity and mortality, and benefits from intervention. However, studies have focused on acute treatment. Thus, data are limited on long-term treatment (ie, both continuation and maintenance treatment). This article discusses the naturalistic course of depression following acute treatment with psychotherapy and the efficacy of long-term psychotherapy for the prevention of relapse and recurrence in depressed children and adolescents.

Treatment with escitalopram but not desipramine decreases escape latency times in a learned helplessness model using juvenile rats

The pharmacological treatment of depression in children and adolescents is different from that of adults due to the lack of efficacy of certain antidepressants in the pediatric age group. Our current understanding of why these differences occur is very limited. To develop more effective treatments, a juvenile animal model of depression was tested to validate it as a possible model to specifically study pediatric depression. Procedures for use with juvenile rats at postnatal day (PND) 21 and 28 were adapted from the adult learned helplessness model in which, 24 h after exposure to inescapable stress, animals are unable to remove themselves from an easily escapable stressor. Rats were treated for 7 days with either the selective serotonin reuptake inhibitor escitalopram at 10 mg/kg or the tricyclic antidepressant desipramine at 3, 10, or 15 mg/kg to determine if treatment could decrease escape latency times. Escitalopram treatment was effective at decreasing escape latency times in all ages tested. Desipramine treatment did not decrease escape latency times for PND 21 rats, but did decrease times for PND 28 and adult animals. The learned helplessness model with PND 21 rats predicts the efficacy of escitalopram and the lack of efficacy of desipramine seen in the treatment of pediatric depression. These findings suggest that the use of PND 21 rats in a modified learned helplessness procedure may be a valuable model of human pediatric depression that can predict pediatric antidepressant efficacy and be used to study antidepressant mechanisms involved in pediatric depression.

Predicting Remission in Depressed Children Treated with Fluoxetine

Fluoxetine is the only antidepressant that has been evaluated for treatment of pediatric depression in more than one randomized controlled trial, and it often is the initial medication selected for treatment of major depression in children and adolescents. Current guidelines suggest a change of medication at 6 to 8 weeks when patients have an insufficient response. To …

Diagnosis, Treatment of Youth for Depression Fell After FDA Alert

These findings, which appeared in the June American Journal of Psychiatry, have heightened the concerns of researchers and clinicians alike that suicide rates among untreated children and adolescents will rise unchecked. In fact, a study published in the February Pediatrics revealed an 18.2 percent increase in suicide from 2003 to 2004 among youngsters under the age of 20 (Psychiatric News, March 2).

Decline in Treatment of Pediatric Depression After FDA Advisory on Risk of Suicidality With SSRIs

In October 2003, the U.S. Food and Drug Administration (FDA) issued a public health advisory about the risk of suicidality in pediatric patients taking selective serotonin reuptake inhibitors (SSRIs) for depression. This study used data from a large national pediatric cohort to examine patterns of diagnosis of depression, prescription of antidepressants, prescription of pharmacological alternatives to antidepressants, and use of psychosocial care before and after the FDA advisory was issued. A large pediatric cohort with newly diagnosed episodes of depression was created from a national integrated claims database of managed care plans from October 1998 to September 2005 (N=65,349). Time-series models were used to compare diagnosing and prescribing trends during the 2 years after the FDA advisory and the expected trends based on data from the 5-year period preceding the advisory. From 1999 to 2004, pediatric diagnoses of depression increased from 3 to 5 per 1,000. After the FDA advisory was issued, the national rate decreased to 1999 levels, a significant deviation from the historical trend. Pediatricians and nonpediatrician primary care physicians accounted for the largest reductions in new diagnoses. Among patients with depression, the proportion receiving no antidepressant increased to three times the rate predicted by the preadvisory trend, and SSRI prescription fills were 58% lower than predicted by the trend. There was no evidence of a significant increase in use of treatment alternatives (psychotherapy, atypical antipsychotics, and anxiolytics). The FDA advisory was associated with significant reductions in aggregate rates of diagnosis and treatment of pediatric depression.

Decline in Treatment of Pediatric Depression After FDA Advisory on Risk of Suicidality With SSRIs

Objective: In October 2003, the U.S. Food and Drug Administration (FDA) issued a public health advisory about the risk of suicidality in pediatric patients taking selective serotonin reuptake inhibitors (SSRIs) for depression. This study used data from a large national pediatric cohort to examine patterns of diagnosis of depression, prescription of antidepressants, prescription of pharmacological alternatives to antidepressants, and use of psychosocial care before and after the FDA advisory was issued. Method: A large pediatric cohort with newly diagnosed episodes of depression was created from a national integrated claims database of managed care plans from October 1998 to September 2005 (N=65,349). Time-series models were used to compare diagnosing and prescribing trends during the 2 years after the FDA advisory and the expected trends based on data from the 5-year period preceding the advisory. Results: From 1999 to 2004, pediatric diagnoses of depression increased from 3 to 5 per 1,000. After the FDA advisory was issued, the national rate decreased to 1999 levels, a significant deviation from the historical trend. Pediatricians and nonpediatrician primary care physicians accounted for the largest reductions in new diagnoses. Among patients with depression, the proportion receiving no antidepressant increased to three times the rate predicted by the preadvisory trend, and SSRI prescription fills were 58% lower than predicted by the trend. There was no evidence of a significant increase in use of treatment alternatives (psychotherapy, atypical antipsychotics, and anxiolytics). Conclusions: The FDA advisory was associated with significant reductions in aggregate rates of diagnosis and treatment of pediatric depression.

The FDA Pediatric Advisories and Changes in Diagnosis and Treatment of Pediatric Depression

The FDA Pediatric Advisories and Changes in Diagnosis and Treatment of Pediatric Depression

Selective Serotonin Reuptake Inhibitors in Pediatric Depression: Is the Balance Between Benefits and Risks Favorable?

Recent controversies surrounding the use of selective serotonin reuptake inhibitors (SSRIs) have highlighted the need to reassess potential benefits, as well as potential risks of this class of medications in the treatment of pediatric depression. The recent availability of data from meta-analyses of published and unpublished antidepressant trials, epidemiological studies, and the Treatment for Adolescents with Depression Study (TADS) has facilitated a reanalysis of this risk/benefit relationship. Despite reviewing similar data, various regulatory agencies have arrived at rather disparate conclusions regarding the data, resulting in continued controversy. Although all groups appear to agree that careful assessment, education regarding risks, and closer monitoring are essential for SSRIs, only the U.S. Food and Drug Administration (FDA) and the U.K. Medicine and Health Care Products Regulatory Agency maintain that an acceptable risk/benefit relationship exists for fluoxetine. The European Medicines Agency concluded that the SSRIs should not be used in the treatment of depression in children and adolescents. The authors of this review have taken into consideration many of these same data and offer a critical discussion of the pros and cons of SSRIs in pediatric depression. The authors have concluded that SSRIs -- in particular, fluoxetine -- do have a role in the treatment of pediatric depression.

A Double-Blind, Randomized, Placebo-Controlled Trial of Escitalopram in the Treatment of Pediatric Depression

Escitalopram is a selective serotonin reuptake inhibitor antidepressant indicated for use in adults. This trial examined the efficacy and safety of escitalopram in pediatric depression. Patients (6-17 years old) with major depressive disorder were randomized to receive 8 weeks of double-blind flexibly dosed treatment with escitalopram (10-20 mg/day; n = 131) or placebo (n = 133). Randomization was not stratified by age. The primary efficacy measure was the mean change from baseline to endpoint in Children's Depression Rating Scale-Revised (CDRS-R) scores, using the last observation carried forward approach. A total of 82% of patients completed treatment. Escitalopram did not significantly improve CDRS-R scores compared to placebo at endpoint (least squares mean difference = -1.7, p = .31; last observation carried forward). In a post hoc analysis of adolescent (ages 12-17 years) completers, escitalopram significantly improved CDRS-R scores compared with placebo (least squares mean difference = -4.6, p = .047). Headache and abdominal pain were the only adverse events in >10% of patients in the escitalopram group. Discontinuation rates caused by adverse events were 1.5% for both groups. Potential suicide-related events were observed in one escitalopram- and two placebo-treated patients. There were no completed suicides. Although there were no significant differences between escitalopram and placebo in the total population, the data suggest that escitalopram may have beneficial effects in adolescent patients. Escitalopram appeared to be well tolerated.

Comparative efficacy of cognitive behavioral therapy, fluoxetine, and their combination in depressed adolescents: Initial lessons from the treatment for adolescents with depression study

Adolescents with major depressive disorder (MDD), their families and clinicians experience significant challenges when weighing the potential risks versus benefits of available choices in the treatment of MDD. Although MDD is highly prevalent in adolescents and is associated with marked suffering, impairment and risk of suicide, the scientific data regarding the safety and efficacy of treatments for pediatric depression are limited. Controlled clinical trials have provided support for the use of psychotherapy and fluoxetine for the treatment of pediatric depression, but until recently no information on the comparative efficacy of these recommended interventions alone or in combination was available. The Treatment for Adolescents with Depression Study provides a very important therapeutic advance in the field by convincingly showing that combination treatment with cognitive behavioral therapy and fluoxetine has the best benefit to risk ratio for adolescents with moderate to severe depression, and is superior to monotherapy. Moreover, the study results confirm that fluoxetine alone is effective in the treatment of depressed adolescents.

Datapoints: Recent Trends in Suicide Among U.S. Adolescent Males, 1992-2001

Back to table of contents Previous article Next article ColumnsFull AccessDatapoints: Recent Trends in Suicide Among U.S. Adolescent Males, 1992-2001Jeffrey A. Bridge, Ph.D., Rémy P. Barbe, M.D., and David A. Brent, M.D.Jeffrey A. BridgeSearch for more papers by this author, Ph.D., Rémy P. BarbeSearch for more papers by this author, M.D., and David A. BrentSearch for more papers by this author, M.D.Published Online:1 May 2005https://doi.org/10.1176/appi.ps.56.5.522AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail In the United States black youths have historically had lower suicide rates than white youths, but the gap has been narrowing because of an increase in the suicide rate among young black males (1).Using the mortality database from the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research (2), we determined trends in suicide deaths between 1992 and 2001 for white males and black males aged 15 to 19 years. Trends in suicide were estimated by using negative binomial rate regression analyses.As Figures 1 and 2 show, the overall suicide rate among white males decreased by an average of 3.9 percent annually (p<.001). The firearm suicide rate decreased by 6.6 percent annually (p<.001), and the rate of suicide by other means decreased by 3.9 percent annually (p=.002). However, there was an annual increase of 3.2 percent for suicide by suffocation (mostly hanging) (p<.001). In contrast, the overall suicide rate among black males decreased by 7.3 percent annually (p<.001), and nearly all the decrease was explained by a 10.2 percent annual decrease in the firearm suicide rate (p<.001).Possible explanations for the recent decline in the youth suicide rate include the enactment of gun laws intended to keep firearms from youths (3) and the increasing use of selective serotonin reuptake inhibitors in the treatment of pediatric depression (1).The firearm suicide rate has fallen substantially in recent years among both white and black adolescent males. This decline may be part of an overall downward trend in firearm deaths (2). The recent increase in suffocation suicides among white male teenagers may indicate that method-specific substitution is occurring. Our data underscore the need for health care providers to assess the availability of lethal means, and the risk for their use, and to make recommendations for their removal or safe storage.AcknowledgmentsThis research was supported in part by grants K01-MH-69948, T32-MH-18951, and P30-MH-66371 from the National Institute of Mental Health and by a grant from the University Hospitals of Geneva.The authors are affiliated with the division of child and adolescent psychiatry at the University of Pittsburgh School of Medicine, 3811 O'Hara Street, Pittsburgh, Pennsylvania 15213-2592 (e-mail, [email protected]). Dr. Barbe is also with the child and adolescent psychiatry service at the University Hospital of Geneva in Switzerland. Harold Alan Pincus, M.D., and Terri L. Tanielian, M.A., are editors of this column.Figure 1. Suicide completion rates among white males aged 15 to 19 years, 1992-2001Figure 2. Suicide completion rates among black males aged 15 to 19 years, 1992-2001

Fallout from the Pharma Scandals: The Loss of Doctors' Credibility?

Last year I attended both Food and Drug Administration (FDA) hearings on children's depression and anti-depressants. Despite my twenty-six years of clinical practice in behavioral-developmental pediatrics, I was unprepared for the impact these meetings had on me. Listening to the testimony of families whose children have committed suicide while taking one of the new antidepressants--the selective serotonin reuptake inhibitors--left the doctors at the hearing shaking their heads, and watching the intricate dance of government, academia, and industry confirmed my worst fears about the relationship between doctors and the industry. The meetings were the culmination of a decade-long pursuit of justice. In the 1994 case of Wesbecker v. Eli Lilly, the family of a man who went berserk, killed several people, and eventually killed himself shortly after starting to take Prozac claimed that Eli Lilly, which manufactures Prozac, knew of its potential side effects and had withheld that information from the public. But when a parade of industry-financed expert witnesses affirmed the safety of the drug, a jury voted nine to three to acquit Eli Lilly. The verdict essentially closed the door to successful legal challenges to Prozac for nearly ten years. Several trial lawyers, convinced of the potential agitating effects of the SSRIs (which include, besides Prozac, Zoloft, Paxil, Celexa, Lexipro, and Effexor), continued to pursue the issue, however. They were joined in the mid1990s by a British research psychiatrist, David Healy, whose analysis of studies funded by the companies demonstrated a consistent signal of increased suicidality--that is, suicidal thinking and behavior. Their persistent efforts were rewarded when, under the Freedom of Information Act, they discovered eight previously undisclosed studies on the SSRIs and childhood depression. The new studies had all been filed with the FDA under the Best Pharmaceuticals for Children Act of 2002, which reflected a congressional effort to motivate companies to study the effects of medications on children. The effort is important because children's metabolism is different and drugs might affect them differently; but since children present a smaller market for new drugs, the pharmaceutical industry might not study them without some prodding. The act rewards the companies that perform pediatric studies by permitting them an extra six months of patent protection, which for a like Zoloft represents an additional billion dollars in sales. However, the law did not require either the companies or the FDA to publicize or publish the findings. In the case of the SSRIs, there were seven existing published studies, of which only three showed that the SSRIs had any benefits over placebo in the treatment of pediatric depression. Healy and company found that all of the eight unpublished studies were negative. When combined with the available public data, the overall numbers clearly showed a lack of effectiveness for the SSRIs and a small but significant increase in rates of suicidality. These results were first presented to the United Kingdom's FDA equivalent, the Medicines and Health Care Regulatory Agency (MHRA). In August of 2003, the MHRA banned the use of most SSRIs for the treatment of childhood depression. The lone exception was Prozac, which had been the subject of the three positive studies. In contrast, there was evidence of much foot-dragging at the FDA, which operates in a very different drug culture. In America, beginning in the early 1990s with stimulant drugs like Ritalin, the pediatric use of all types of psychiatric drugs has skyrocketed. For both ideological and economic reasons, the practices of American child psychiatrists changed dramatically over the decade, so that by 2002 nine out of ten children treated by a child psychiatrist were taking one or more psychiatric drugs. In comparison, European child psychiatrists, pediatricians, and family practitioners (who have an important role in child health care in the United Kingdom) are far more parsimonious than their American colleagues with the pediatric use of psychiatric medications. …