Featured Report:
Safety and Efficacy of Selective Serotonin Reuptake Inhibitors (SSRIs) in Children and Adolescents (A-05)
Full Text

Introduction and Methods
Drug Use in Pediatric Patients-Pediatric Drug Labeling and Unlabeled Uses
Concerns About Antidepressant-related Suicidality
Suicide
Antidepressant-related Suicidality in Children and Adolescents
Efficacy of Antidepressants in Children and Adolescents
Obsessive-Compulsive Disorder
Other Anxiety Disorders
Major Depressive Disorder
Use of Tricyclic Antidepressants (TCAs
Use of SSRIs
The Treatment for Adolescents with Depression Study (TADS)
Depression and Suicide in Children and Adolescents
Examinations of the Relationship between Antidepressants and Suicide
Use of National Population Data Sets
Patient-level Controlled Observational Studies
Health Insurance Claims Database
Clinical Trial Datasets
FDA Analysis of Antidepressant Use and Suicidality
Office of Drug Safety Analysis
Columbia Review
FDA Meta-analysis of Columbia Classified Data
Other Safety Issues with SSRIs
Summary and Comment
Recommendations (Adopted AMA policy and directives)
References
Appendices (PDF, 134 KB, requires Adobe® Reader®)

Resolution 803 (I-04), introduced by the American Academy of Child and Adolescent Psychiatry and the American Psychiatric Association and adopted by the House of Delegates at the 2004 American Medical Association Annual Meeting, asked that the Council on Scientific Affairs (CSA) work in conjunction with all appropriate specialty societies to prepare an independent, comprehensive review of the scientific data currently available pertaining to the safety and efficacy of the use of selective serotonin reuptake inhibitor (SSRI) antidepressants in the treatment of child and adolescent psychiatric disorders.  These antidepressants include fluoxetine (Prozac®), sertraline (Zoloft®), paroxetine (Paxil®), fluvoxamine (Luvox®), and citalopram (Celexa®).

This issue deserves scrutiny because of recent actions taken worldwide by drug regulatory agencies to discourage the use of such products in children and adolescents and/or issue warnings about their use in such patients based on concerns about a possible link between use of antidepressant medication and suicidality (ie, suicidal ideation or attempts) in pediatric patients.  In the United States this included the introduction of a Black Box warning in the product labeling for antidepressant drugs.  These regulatory actions were prompted, in part, by an extensive review of unpublished data from clinical trials involving the use of antidepressants in children and adolescents.  The existence of several unpublished clinical trial reports reinforced a longstanding concern about the adequacy of the evidence base supporting the therapeutic use of many drugs in pediatric patients, as well as the information contained in the Pediatric Use sections of prescription drug labels (package insert).  This information is used to assist physicians in implementing drug therapy in pediatric patients in a safe and effective manner.

Accordingly, this report: (1) briefly reviews recent approaches used in the United States to enhance pediatric prescription drug labeling;  (2) recounts recent regulatory actions on the use of antidepressants in children and adolescents;  (3) evaluates the apparent safety and efficacy of antidepressants, particularly the SSRIs, in children and adolescents; and (4)  reviews the evidence on whether these drugs may have a causal role in the emergence of suicidality during treatment.

Methods

Literature searches were conducted in the MEDLINE database for English-language articles published between 1990 and April 2005 using the search terms antidepressant, serotonin reuptake inhibitor, SSRI, fluoxetine, paroxetine, sertraline, citalopram, or fluvoxamine, in combination with suicide or self-harm and  child, teen, or adolescent.  This search yielded 986 references, 306 of which were deemed relevant to this report. The background material, presentations, and proceedings from the deliberations of the U.S. Food and Drug Administration (FDA) Psychopharmacologic Drugs and Pediatric Advisory Committees and the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) also were consulted. Back to top

Drug Use in Pediatric Patients─Pediatric Drug Labeling and Unlabeled Uses

As part of its regulatory function in approving drug products for marketing in the United States, the FDA also approves each drug product's labeling; ie, container label, package insert, and certain advertising.  This is referred to as FDA-approved labeling.  Unlabeled uses are defined as the use of a drug product for indications or in patient populations, doses, or routes of administration that are not included in FDA-approved labeling.  Under the federal Food, Drug, and Cosmetic (FD&C) Act, a drug approved by the FDA for marketing may be labeled, promoted, and advertised by a manufacturer for only those uses for which the drug’s safety and efficacy have been established.  However, the FD&C Act does not limit the manner in which a physician may use an FDA-approved drug.  A physician may choose to prescribe a drug for uses or in treatment regimens or patient populations that are not in approved labeling. This decision is made by the physician in light of all information available and in the best interests of the individual patient.  Prescribing for an unlabeled use only requires the physician to use the same judgment and prudence as exercised in medical practice in general for it to conform to accepted professional standards.  The issue of unlabeled uses was previously examined by the CSA.¹

Historically, unlabeled uses have been especially common in pediatrics, primarily because of the lack of clinical trials conducted on pediatric patients.  Efforts to improve the development of credible pediatric drug information began more than 30 years ago with an American Academy of Pediatrics (AAP) report commissioned by the FDA entitled General Guidelines for the Evaluation of Drugs to be Approved for Use During Pregnancy and for Treatment of Infants and Children, and the FDA guidance General Considerations for the Clinical Evaluation of Drugs in Infants and Children.  Subsequently, an FDA regulation established the Pediatric Use subsection of the package insert within the Precautions section (21 CFR 201.57 (f)(9)).   In 1994, in an effort to update pediatric use information in the label, the FDA required sponsors to submit all pediatric studies and information they had obtained in the pediatric population. In addition, the agency defined another route (extrapolation) for establishing pediatric efficacy for a product used in both adults and pediatric patients. The process of extrapolation of efficacy from adult data is based on the premise that the disease and the response to therapy are expected to be sufficiently similar in adults and pediatric patients to permit such extrapolation.  In 1996, an FDA guidance, the Content and Format of Pediatric Use Section, provided further information intended to improve prescription drug labeling. 

Over the last decade, many clinical trials have been conducted in pediatric patients. The data from these trials have been used to establish FDA-approved pediatric indications for many drugs, and to generally enhance pediatric drug information.  Three legislative initiatives were instrumental in driving this practice.  In 1998, the FDA implemented a regulation (pediatric rule) that allowed the agency to require pediatric studies in certain situations.  Although this regulation was enjoined by a court in 2002, it was later reconstructed into law by Congress in the Pediatric Research Equity Act of 2003.  Most importantly, the Food and Drug Administration Modernization Act of 1997 (FDAMA) and later the Best Pharmaceuticals for Children Act of 2002 (BPCA), respectively, authorized and reauthorized the FDA to grant an additional 6 months of marketing exclusivity (referred to as pediatric exclusivity) to pharmaceutical manufacturers who voluntarily conducted studies of their drugs in pediatric populations.  Under FDAMA, and now the BPCA, either the sponsor submits a pediatric study proposal that the FDA reviews or the FDA initiates and issues a written request directly to sponsors to conduct studies in the pediatric population for drugs with existing marketing exclusivity and/or patent protection.  Once the sponsor completes and submits the study(ies) to the FDA, eligibility for pediatric exclusivity is reviewed and a determination is made whether the sponsor should receive the additional exclusivity.   Although these clinical trials are not required to demonstrate efficacy in order to be eligible for additional marketing exclusivity, they are required to fairly respond to the terms of the written request as issued by the FDA.  With the enactment of BPCA, these studies are now required to have public dissemination (see below).  Virtually all of the studies reviewed as part of the deliberations for the September 2004 meeting of the FDA’s Psychopharmacologic Drugs Advisory Committee (PDAC) and Pediatric Advisory Committee on “Suicidality in Clinical Trials for Antidepressant Drugs in Pediatric Patients'' were conducted in pursuit of pediatric exclusivity (see below).

As noted above, under current FDA regulations, a new indication in a pediatric population can be established by extrapolating the efficacy results of adequate and well-controlled studies in adults for the same indication, if for example it is believed that the condition/disease is essentially the same disease in adults and children. Pharmacokinetic and safety data in the affected pediatric population will generally be required as supporting information.  Under FDAMA and BPCA, a new indication also might be based on a single study in pediatric patients along with confirmatory evidence from another source, perhaps adult data for that disorder.  This approach also requires some degree of certainty that the course of the disease is sufficiently similar in pediatric and adult populations.  In the FDA’s view, this is not the case for depression; therefore, a pediatric depression indication for any antidepressant already approved for such use in adults would need to be supported by 2 independent, adequate and well-controlled clinical trials in pediatric depression, along with pharmacokinetic and safety information.  For pediatric depression the relevant age groups are considered to include children (aged 7 to 11 years) and adolescents (aged 12 to 17 years).

The BPCA also established a mechanism for obtaining information in the pediatric population for off-patent drugs (off-patent study process).  The off-patent study process is driven by a priority list of drugs for which pediatric studies are needed that is developed by the National Institutes of Health (NIH), in consultation with the FDA and other experts in pediatric research (eg, American Academy of Pediatrics, U.S. Pharmacopoeia), and published annually in the Federal Register.  If the industry declines to conduct studies in response to a written request issued by the FDA, the written request is referred to the NIH for contract and study. Back to top

Concerns About Antidepressant-related Suicidality

The occurrence of suicidal thoughts and suicide attempts in patients with major depressive disorder, as well as other psychiatric illnesses, is not a new concern.  The potential relationship of suicidality to treatment and the need for close supervision has been previously noted in the product labeling for antidepressant drugs under the Precautions section.

Suicide: The possibility of a suicide attempt is inherent in major depressive disorder and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy. Prescriptions for “Antidepressant X” should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

As noted in the background material supplied for the February 2004 joint meeting of the PDAC and Pediatric Advisory Committee, beginning with the availability of the tricyclic antidepressant drugs in the 1960s, reference textbooks recognized the concept that with the initiation of treatment the risk of increased suicidality may emerge.² 

 With beginning convalescence (following initiation of treatment with tricyclic  antidepressants), the risk of suicide once more becomes serious as retardation fades.³

This concept received renewed attention in 1990 with the publication of a case series involving adult patients, which suggested they became suicidal as a result of being treated with fluoxetine.⁴  The issue of whether fluoxetine and other antidepressants may trigger an increase in suicidality, particularly early in treatment, was deliberated by the PDAC in 1991.⁵ As part of this deliberation, the existence of treatment-emergent suicidality was again noted and several mechanisms were proposed to account for its occurrence, including worsening of depression; induction of conditions (eg, akathisia, anxiety, panic, or insomnia) that can lead to suicidal behavior; and stage shifts in patients with bipolar disorder.²  Evaluation of the existing clinical trial database in adults exposed to fluoxetine was reassuring with respect to antidepressant-induced suicidality, and the PDAC took no action at that time.^5,6  No significant controlled safety data on children and adolescents treated with fluoxetine were available at that time.  However, the notion persisted that individual patients, including children and adolescents, may be at unique risk for treatment-emergent suicidality with fluoxetine.^7-12    The American Psychiatric Association notes in its 2002 Practice Guideline for the treatment of patients with major depressive disorder that with implementation of pharmacotherapy, “[patient] visits should [also] be frequent enough to monitor and address suicidality.”¹³

Antidepressant-related Suicidality in Children and Adolescents.  Recent concern about a possible link between antidepressant medication and suicidal behavior (suicidal attempts or ideation) in pediatric patients has focused on the current generation of antidepressant drugs, including, among others, the SSRIs and the serotonin/norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine (Effexor®). 

An FDA review of a pediatric application for paroxetine led to the suspicion that adverse events suggestive of suicidality were included, along with other events, under the term “emotional lability” in clinical trial adverse event reports.  This led to a reexamination of the clinical trial data for paroxetine, as well as other antidepressants, for adverse events related to suicidality (see below).  The review culminated in various actions taken by drug regulatory agencies worldwide intended to either discourage the use of these drugs in children and adolescents, or to introduce substantial warnings into the product labeling.  The timeline of these events, and a summary of the regulatory actions can be found in Appendix 1 (PDF, 134KB, requires Adobe® Reader®).  A copy of the Black Box warning currently required by the FDA for all antidepressants can be found in Appendix 2 (PDF, 134 KB).  A copy of the FDA-mandated Patient Medication Guide (MedGuide), which primarily emphasizes the risk of suicidality and which must be given to patients when an antidepressant medication is dispensed can be found in Appendix 3 (PDF, 134 KB.  Additional (class) labeling changes were also required by the FDA in the Warnings and Precautions sections of the package insert for all antidepressant drugs to caution practitioners, patients, family members or caregivers about treatment-emergent suicidality, including a directive on the frequency of monitoring that is generally recommended during the first few months of therapy.  A sample template of the revised labeling is available at www.fda.gov/cder/drug/antidepressants/PI_template.pdf (PDF, 96 KB).  Concern has been raised about the recommendation for face-to-face contacts in the first 12 weeks of therapy, inasmuch as many physicians know their patients and families very well and could garner reliable information through telephone contact rather than through required office visits, as well as the potential impact of the Black Box and MedGuide on patient access and compliance with treatment. 

Because these regulatory actions involved examination of the benefit-risk balance of antidepressant use in pediatric patients, the following sections of this report examine both the efficacy and safety of antidepressants in pediatric patients, particularly the SSRIs. Back to top

Efficacy of Antidepressants in Children and Adolescents

First introduced in the late 1980s, SSRIs have been used to treat mood disorders (eg, major depression) as well as other psychiatric and mental disorders in children and adolescents.  These include, most notably, obsessive-compulsive disorder, but also other anxiety disorders, attention deficit hyperactivity disorder, and social phobia.  Prescription rates for these agents have increased markedly over the last 15 years, and SSRIs are commonly prescribed off-label to pediatric patients for the treatment of major depression, anxiety, and other psychiatric disorders.^14-16  The SSRIs are considered to represent a substantial improvement over older tricyclic antidepressants (TCAs) because they are better tolerated and are much safer in overdose.¹⁷  Fluoxetine is the only antidepressant approved by the FDA for the treatment of major depressive disorder in patients 8 years of age or older. 

Obsessive-Compulsive Disorder.  Fluvoxamine, sertraline, fluoxetine, and clomipramine (a TCA with prominent serotonin reuptake inhibiting properties) are approved by the FDA for the treatment of obsessive-compulsive disorder (OCD) in children and adolescents and their benefit-risk balance appears to be favorable for the treatment of this condition.^18-24   Paroxetine is not approved for any pediatric indication but trials have been conducted that demonstrated its efficacy in OCD, and the sponsor is seeking FDA approval for use in this condition.²⁵  Cognitive-behavior therapy (CBT) is a well-documented intervention for adults with OCD.²⁶   Prospective studies suggest that CBT also is useful for pediatric OCD.^27,28  The multicenter Pediatric OCD Treatment Study funded by the National Institute of Mental Health (NIMH) evaluated the efficacy of CBT alone, medication management with sertraline alone, or their combination as the initial treatment of children and adolescents with OCD.  Both CBT and sertraline were more effective than placebo, but the combination of CBT with sertraline was the most effective intervention.²⁹

Other Anxiety Disorders.  In controlled trials, fluvoxamine and fluoxetine have demonstrated efficacy for generalized anxiety disorder, separation anxiety disorder, and social phobia; paroxetine has demonstrated efficacy in children and adolescents with social anxiety disorder, and in a small placebo-controlled trial, sertraline was effective in children and adolescents with generalized anxiety disorder. ^30-33 None of these agents have FDA approval for treatment of these disorders.

Major Depressive Disorder.  Epidemiologic studies have shown that major depressive disorder (MDD) has a prevalence of 2% in children and 4% to 8% in adolescents.³⁴ This disorder tends to be an episodic, recurrent illness.  Although most children with depression have symptoms similar to those seen in adults, such as sad mood, apathy, lack of energy, and vegetative signs, in some children the disorder is manifested primarily by irritability or social isolation.³⁴  The clinical picture varies across different developmental stages.  Children may exhibit more symptoms of anxiety and somatic complaints, and may express irritability and frustration with temper tantrums and behavioral problems instead of verbalizing feelings.  Suicidal ideation and serious suicide attempts are less frequent in children compared with adolescents; the latter tend to display more sleep and appetite disturbances, delusions, and impairment of functioning than younger children.

A recent study that prospectively compared the clinical presentation, course, and parental psychiatric history of children and adolescents with MDD found that both groups had similar depressive symptomatology, duration, severity of the index episode, rates of recovery (85%) and recurrence (40%), comorbid disorders, and parental psychiatric history, although adolescents suffered from more depressive melancholic symptoms.  Female sex, increased guilt, prior episodes of depression, and parental psychopathology were associated with a worse longitudinal course.³⁵

A practice parameter issued by the American Academy of Child and Adolescent Psychiatry recommends psychosocial and pharmacologic intervention for MDD, with psychotherapy as the preferred initial intervention for most youth.34  Psychological treatments, including CBT and interpersonal psychotherapy, are effective in a subset of individuals with mild or moderately severe depression.^36-40  Combining medication and psychological treatment may be the most effective intervention.⁴¹

Use of Tricyclic Antidepressants (TCAs).  Evaluation of the use of SSRIs in pediatric patients must be prefaced by discussion of earlier investigations of TCAs to treat depression in children and adolescents.  Pilot studies conducted in the 1980s and early 1990s with TCAs were marked by failure to demonstrate efficacy.  These trials were characterized by small samples sizes, and some included adolescents with severe depression or treatment-resistant patients.  A meta-analysis of 12 controlled trials that were conducted between 1980 and 1992 concluded that TCAs were not efficacious in children and adolescents with MDD.⁴²  Fewer than 300 subjects were included in these trials and meta-analysis.  However, 4 subsequent trials also reported negative results.^43-46  These findings, combined with concerns about the relative tolerability of TCAs; their potential for cardiac toxicity, both at therapeutic doses and in overdose; and lethality in overdose convinced most clinical investigators and practitioners that their clinical value was minimal in children and adolescents with depression.  A recent Cochrane systematic review also concluded that TCAs are not useful in treating depression in prepubertal children and that there is only marginal evidence to support their use in the treatment of depression in adolescents.⁴⁷

Use of SSRIs.   With the approval of a number of SSRIs for use in adults, they and other newer antidepressants, such as venlafaxine, became the focus of investigation for the treatment of MDD in children and adolescents.  The pediatric exclusivity provisions of FDAMA and the BPCA provided the incentive to conduct these clinical trials.

As part of the deliberations of the September 2004 joint meeting of the FDA’s PDAC and Pediatric Advisory Committee, the joint committee reviewed information from 9 antidepressant drug development programs, most done for pediatric exclusivity.  The committee also reviewed data from two other studies involving another antidepressant drug for which the studies were not done for exclusivity.  Overall, the committee reviewed data from 24 studies for 9 antidepressant drugs involving more than 4400 pediatric subjects. The 9 drugs included 5 SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram), as well as bupropion (Wellbutrin®), venlafaxine, nefazodone (Serzone®), and mirtazapine (Remeron®).  Fifteen of these studies were in subjects with MDD (all conducted in pursuit of pediatric exclusivity), 4 in OCD, 2 in generalized anxiety disorder, one in social anxiety disorder, and 2 in attention deficit hyperactivity disorder. 

The 15 MDD trials utilized a randomized, double-blind, placebo-controlled, flexible-dose, parallel group design involving outpatients (both children and adolescents).  These trials are summarized briefly in Appendix 4 (PDF, 134 KB).  One of the trials involving citalopram allowed inpatients with depression to be enrolled, and one trial involving paroxetine utilized an active comparator (imipramine).  Depending on the time period, either Diagnostic and Statistical Manual (DSM) III, DSM III-R, or DSM IV diagnostic criteria for major depression were used to screen subjects for study eligibility.  Inclusion criteria for depression relied on use of the Children’s Depression Rating Scale-revised (CDRS-R); a few relied on the Hamilton Depression Scale (HAM-D), Montgomery Asberg Depression Rating Scale (MADRS), or the Beck Depression Inventory (BDI).  Treatment duration of the blinded phase lasted anywhere from 8 to 12 weeks.  Most of these trials excluded patients who were considered a serious suicidal risk, which was variably defined as: (1) the presence of serious suicidal ideation or ideation with a definite plan; (2) a suicide attempt within the current depressive episode, the past year, or that resulted in hospitalization; or (3) being acutely suicidal to the degree that precautions against suicide were required.  Most trials also excluded patients with bipolar disorder, psychotic symptoms, and a history of alcohol and drug abuse or eating disorders, but accepted patients with borderline personality disorder. 

The results from 6 of these trials, as well as 2 others, have been published in the peer-reviewed medical literature.^48-54   One publication pooled the results of 2 trials involving sertraline.⁵¹  The BCPA requires that the FDA Commissioner “shall make available to the public a summary of the medical and clinical pharmacology reviews of pediatric studies conducted within 180 days of submission of a pediatric study.”  The summaries for venlafaxine, paroxetine, nefazadone, citalopram, sertraline, and mirtazapine are available on the pediatric summary review site: www.fda.gov/cder/pediatric/summaryreview.htm.  Under the FDA’s general disclosure provisions for approved applications, the summary for fluoxetine is available at: http://www.fda.gov/cder/foi/nda/2003/18936s064_Prozac.htm.

On an individual basis, 2 trials involving fluoxetine and one involving citalopram satisfied the FDA’s criteria for demonstrating efficacy.^49-51 A long-term follow-up study of fluoxetine responders, found that the drug also protected subjects from relapse compared with placebo.⁵⁵  One trial involving paroxetine was significant on one primary outcome measure, and on several secondary measures.⁵²  Perhaps of note, the 2 positive fluoxetine studies used a more extensive screening process, requiring verification of diagnosis and study eligibility by at least 2 independent clinicians. As mentioned, one publication pooled the results of 2 separate but identical trials involving sertraline.⁵³  In the individual trials, sertraline was not significantly different from placebo, but when the results were pooled, a statistically significant difference in the response rate for sertraline recipients occurred (sertraline 69%; placebo 59%) with responders defined as those who experienced  ≥40% decrease in CDRS-R total scores from baseline.  Subgroup analysis based on age stratification showed a very high placebo response rate in the 6 to 11 years age group with no separation of sertraline from placebo, but a larger, and significant, difference in treatment response was apparent when analyzing the 12- to 17-year-old age group.⁵⁶  These results suggest that children may be more responsive to the nonspecific measures of support that are included in the placebo response, possibly because children (and some adolescents) are in a more dependent and reactive developmental state.  In any event, the FDA rejected the sponsor’s submission of the pooled analysis seeking approval of sertraline in pediatric MDD on the basis that 2 separate adequate and well-controlled trials must demonstrate efficacy.

Added to the lack of demonstrated efficacy for TCAs in pediatric MDD, the fact that only 3 of 15 trials of SSRIs and newer antidepressants in children and adolescents were able to demonstrate efficacy on the primary outcome measure is a cause for concern.  Only SSRI trials reporting positive results on some measures have been published in the peer-reviewed medical literature.  A meta-analysis of both published and unpublished data for the SSRIs and venlafaxine concluded that the benefit-risk balance for their use in children and adolescents was minimal except for fluoxetine and likely to have been overestimated because the published studies had much more favorable results than the unpublished studies.⁵⁷
Discussion.  Pediatric antidepressants drug trials may fail for different reasons, in addition to lack of efficacy.  Although the more recent trials involving SSRIs and newer antidepressants included more patients than earlier trials involving the TCAs, certain limitations of trials conducted in pursuit of pediatric exclusivity have been noted. The pediatric trials of antidepressants were based on available experience from adult studies and were adequately powered for efficacy based on the effect size seen in the adult studies.  However, their relatively small sample size is relevant if differences in response may be occurring in subsets of the pediatric population.  The fact that data were gathered over a large developmental range with no a priori stratification in relation to age or severity of the illness, both likely predictors of outcome, may contribute to the inability to differentiate an effect.  It seems likely that combining prepubertal children (higher placebo responses) and postpubertal adolescents into a single population in order to achieve an adequate number of trial participants may have reduced the probability that efficacy could be demonstrated in older subjects. This hypothesis assumes maturational differences are related to different levels of responsiveness.

These trials also varied significantly with respect to certain critical aspects of the sample subjects (eg, previous suicidal behavior; prior use of psychotropic medications; family psychiatric history; co-existing medication drug use possibly affecting SSRI metabolism or side-effects).  Additionally, there was generally limited follow-up of study drop-outs, who may have been at risk for suicidality (see below).  The individual studies were not adequately powered to detect an increased risk of suicidality or other rare serious adverse events.  A summary of the trial characteristics is available at www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1.htm

The lack of typical phase 2 dose-finding studies and the pharmacokinetics of SSRIs in pediatric subjects introduces another element of uncertainty, although the pharmacokinetics of sertraline appear to be similar in children and adolescents compared with adults.⁵⁸  Paroxetine is cleared more rapidly in youths, but demonstrates large interindividual variability, including slow elimination and drug accumulation in individuals who are deficient in cytochrome P4502D6.⁵⁹  The latter phenotype exists in 5% to 10% of the Caucasian population. Also, paroxetine disposition is dose-dependent.  Doubling the dose from 10 to 20 mg per day increases blood concentrations 6-fold.⁵⁹    These features may contribute to drug accumulation and toxicity in some paroxetine recipients. The pharmacokinetics of citalopram and its active metabolites also demonstrate pronounced interindividual variability in adolescents that is influenced by sex, smoking status, and oral contraceptive use.⁶⁰  With respect to fluoxetine, children develop higher concentrations of fluoxetine and its active metabolite norfluoxetine than adolescents, although when normalized for body weight, concentrations are similar.⁶¹  The accumulation profile and steady-state concentrations of fluoxetine in adolescents appear to be similar to those in adults.

On the other hand, the results of some of the positive clinical trials also have been criticized on scientific grounds for the use of post hoc analysis, and lack of consistent efficacy on secondary outcome measures and global improvement scores.  Additionally, the clinical relevance of statistically significant but small absolute changes in CDRS-R scores has been questioned.^62-65   Questions also have been raised about the external validity of these studies because the exclusion criteria precluded the participation of many children and adolescents who would have received SSRIs in actual clinical practice.  Nevertheless, the magnitude of the drug vs. placebo response rates in fluoxetine studies (56% vs 33%; 65% vs 53%; and 61% vs 35% in the Treatment for Adolescents with Depression Study [see below]) are not substantially different from those obtained in antidepressant studies in adults where antidepressants are moderately effective, trials are also characterized by a high rate of placebo response, and approximately one-third of patients derive no apparent benefit.⁶⁶

Accordingly, disagreements persist about the overall strength of the evidence base supporting the use of SSRIs in pediatric patients with depression, based largely on the clinical trials that have been conducted to garner pediatric exclusivity. ^66-69  

As noted in the October 23, 2003, Public Health Advisory issued by the FDA:

[The] FDA emphasizes that, for the 7 drugs evaluated in pediatric major depressive disorder (MDD), data reviewed by FDA were adequate to establish effectiveness in MDD for only one of these drugs (fluoxetine).  Failure to show effectiveness in any particular study in pediatric MDD, however, is not definitive evidence that the drug is not effective since trials may fail for many reasons.  FDA recognizes that pediatric MDD is a serious condition for which there are few established treatment options, and that clinicians often must make choices among treatments available for adult MDD.

The Treatment for Adolescents with Depression Study (TADS).   In contrast to trials conducted by sponsors to support pediatric exclusivity, TADS was a randomized controlled multicenter trial funded by the NIMH.³⁹  Also in contrast to several prior trials, no patients under 12 years of age were enrolled. Subjects were aged 12 to 17 years, had moderate to severe depression based on CDRS-R scores (average episode duration >1 year), and more than one-quarter had at least minimal suicidal ideation at baseline.  The objective of TADS was to examine the effectiveness of medication and cognitive-behavioral psychotherapy, alone and in combination, for the acute and long-term treatment of adolescents with DSM-IV major depression.  Patients were excluded if they had been hospitalized within the previous 3 months for suicidal behavior, or were deemed at high risk (ie, suicidal action within 6 months; suicidal intent or active plan; presence of suicidal ideation within the context of a disorganized family environment).  However, nearly 30% of the subjects enrolled had some suicidal ideation at baseline. This study monitored patients prospectively for harm and suicide-related events, and suicide attempts.

Trials arms included treatment for 12 weeks with fluoxetine (10 to 40 mg daily) or placebo with clinical management (ie, physician visits to monitor clinical status and medication effects), 15 sessions of CBT, or the combination of fluoxetine with CBT.  After 12 weeks of treatment, based on those who were much or very much improved as reflected by Clinical Global Impression scores, the response rate with fluoxetine + CBT (71%) was superior to fluoxetine alone (61%), which was superior to either CBT alone (43%) or placebo (35%).  Based on the slope of changes in total CDRS-R scores across 12 weeks of treatment, fluoxetine recipients and placebo recipients exhibited a similar degree of improvement.  Suicidal ideation based on a suicidal ideation rating scale declined in all treatment groups, but was not different for the fluoxetine alone and placebo recipients.  The occurrence of harm-related events (self-harm; harm to another person or property; increase in suicidal ideation without self-harm; suicide attempt of any lethality) was increased in fluoxetine recipients (odds ratio 2.19) compared with those who received CBT alone or placebo. The appearance of a suicide-related event (ie, worsening of suicidal ideation or making a suicide attempt) occurred in ~6% of patients, with no significant difference in the odds ratio among treatment groups.  Thus, taking both benefit and risk into account, the combination of fluoxetine and CBT was the most effective short-term treatment for MDD in this adolescent population.  Fluoxetine did not increase suicidal ideation, but adverse events related to self-harm occurred more often in fluoxetine recipients. Back to top

Depression and Suicide in Children and Adolescents

Depression is an illness associated with agitation, despair, self-loathing, and suicide. Biological, psychological, social, and cultural factors all have a significant impact on the risk of suicide; however, more than 90% of suicides in the United States are associated with psychiatric illness.  Depression is the single most important risk factor for adolescent suicide although it often acts in concert with substance abuse and impulsive aggression.⁷⁰  In some patients, suicide attempts may occur as depression is lifting and an individual is energized enough to act on thoughts of self-harm.  In addition, treatment with antidepressants may unmask an underlying bipolar disorder, which can result in the induction of a mixed manic and depressive state─a condition that carries a higher risk of suicidal behavior.

Suicidal thoughts and suicidal ideation are not uncommon in children and adolescents of both sexes.  The Centers for Disease Control and Prevention conducts the Youth Risk and Behavior Surveillance System (YRBSS).  The YRBSS conducts surveys among students in most states and the District of Columbia, assessing between 10,000 and 18,000 subjects every other year.  Data from the YRBSS indicate that ~17% of high school students (grades 9-12) reported seriously considering suicide and/or made a suicide plan in 2003.  Approximately 8.5% made a suicide attempt.  Nevertheless, the suicide rate among adolescents has been decreasing over the last decade for the first time in more than half a century (from 6.2 to 4.6 per 100,000 population), although suicide still ranks as the third leading cause of death among persons aged 10 to19 years. 

Depression may be associated with disabling anxiety and thoughts of suicide in 40% to 80% of youth with the illness and 16% to 35% of depressed youth may attempt suicide.⁷¹    Suicidal ideation may be increased by the presence of disruptive disorders, substance abuse, separation anxiety,  mood and anxiety disorders, panic attacks, and “aggressiveness” in males.  Previous suicidal behavior and current suicidal thoughts are significant risk factors for suicide and must be taken seriously.  Previous self-harm also is an important predictor of further self-harm and suicide.⁷⁰  For further information on the epidemiology and risk factors of adolescent suicide see the practice parameter on this subject issued by the American Academy of Child and Adolescent Psychiatry and the policy statement of the American Academy of Pediatrics.^73,74 Back to top

Examinations of the Relationship between Antidepressants and Suicide

In contrast to the concern that initiation of treatment with antidepressants may trigger suicidal behavior, several studies in depressed patients (primarily adults) support the notion that, in fact, suicides are more typically associated with no or inadequate treatment with antidepressants.^75-80  In one retrospective analysis of adult patients suffering from major depression or dysthymia and treated with antidepressants, suicidal behavior increased substantially after discontinuation of treatment with either SSRIs or TCAs.⁸¹  In a recent case-controlled forensic analysis of nearly 15,000 suicides, the presence of different antidepressants was determined.  Overall, the odds ratio for the presence of SSRIs was lower than for other antidepressants. No SSRIs were detected in the 52 suicides that occurred in individuals younger than 15 years of age.  In the 15- to 19-year-old age group, SSRIs were detected less often than non-SSRIs.  These findings do not lend support to the notion that treatment of adolescents or adults with SSRIs leads to an increased risk of suicide.⁸²

Use of National Population Data Sets.  On an international scale, with the use of national population data sets, ecologic evidence suggests that increasing antidepressant use over the last 20 years (as measured by prescription rates) has been associated with a decrease in suicide rates  in Europe, Scandinavia, Australia, and the United States,83-87 although studies in Japan and Iceland did not support this association.^88,89  This type of correlation does not imply a causal relationship; numerous factors may be coincidental, including selection bias, and the fact that the SSRIs are safer in overdose than TCAs. 

Between 1985 and 1999, the suicide rate fell approximately 13.5% in the United States.  One study examined the relationship between suicide and SSRI prescription rates in the United States over this period while adjusting for 2 other factors known to be associated with suicide (unemployment and alcoholic beverage consumption).⁹⁰ SSRI prescription rates were inversely associated with the national suicide rate and were associated with a lower risk of suicide by antidepressant overdose than with TCAs.  Another U.S. study in youth aged 10 to 19 years examined the relationship between regional antidepressant medication treatment and suicide rate stratified by sex, age, median income, and racial composition.  Overall, increased use of antidepressants among youth 10 to 19 years of age was associated with a significant decrease in the suicide rate in this age group.  For each 1% increase in the use of SSRIs among youth, there was a decrease of 0.23 suicides per 100,000 adolescents per year. ⁹¹ Significant inverse relationships were present among males and adolescents aged 15 to 19 years.

Patient-level Controlled Observational Studies.  The most comprehensive studies of suicidal behavior in general practice emanate from the U.K. General Practice Research Database.  This database contains more than 3 million patients enrolled since 1987 with selected general practitioners who have agreed to provide anonymous, comprehensive medical record data for research purposes.  The first study analyzed the risks of suicide in patients who had received at least one prescription for one or more antidepressants between 1988 and 1993 in the 6 months before they died. This study found an increased risk of suicide in fluoxetine recipients, which may have been explained by selection bias. That is, fluoxetine’s relative safety in overdose compared with TCAs may have led to selective prescription to people at greater risk of self-harm.⁹²  This study did not stratify results for children and adolescents.

Another study compared the risks for suicide and nonfatal suicidal behavior among people prescribed fluoxetine, paroxetine, amitryptiline, and dothiepin from 1993 to 1999.⁹³ No notable differences were found among the drugs in risk for fatal or nonfatal suicidal behavior, including the subset of patients aged 10 to 19 years.  However, the risk of suicidal behavior was increased in the first month after starting an antidepressant, especially during the first 1 to 9 days, supporting the concept of a higher risk period with initiation of treatment. This study was not restricted to patients prescribed antidepressants for the treatment of depression.

A third nested case-control study of patients aged 90 years or younger with a new diagnosis of depression who were prescribed antidepressants for the first time between 1995 and 2001 compared the risk of nonfatal self-harm and suicide in association with the use of SSRIs and TCAs.⁹⁴ Overall, in SSRI recipients, the adjusted odds ratio of nonfatal self-harm in SSRI recipients was 0.99 and of suicide 0.57 compared with those prescribed TCAs.  However, the adjusted odds ratio of nonfatal self-harm was 1.59 in SSRI recipients aged 18 years or younger; among SSRIs the greatest risk was associated with paroxetine. No suicides occurred in those aged 18 years or younger with a first prescription of an antidepressant.

Health Insurance Claims Database.  One recent study examined the relationship between prescriptions and suicide attempts by conducting a retrospective longitudinal cohort analysis of paid insurance claims from a managed care database for all health care and prescriptions filled for adolescents aged 12 to 18 years who were newly diagnosed with MDD and had at least 6 months of follow-up data.⁹⁵  In this study, prescriptions for antidepressant medication (SSRIs or other antidepressants) had no significant effect on the likelihood of a suicide attempt.

Clinical Trial Datasets.  Four studies have examined randomized controlled trials in a systematic fashion to establish whether an association exists between the use of SSRIs and/or other antidepressants and suicide attempts.^96-99 These trials are described in Appendix 5 (PDF, 134 KB).  Three trials found no association between antidepressants and suicide attempts. These trials did not parcel out children and adolescents and included clinical trials for indications other than MDD.  The largest study found that SSRIs increased the risk of a suicide attempt but appeared to decrease the risk of a fatal suicide, particularly in patients suffering from MDD.⁹⁹ Back to top

FDA Analysis of Antidepressant Use and Suicidality

Because suicide is rare in children and adolescents, ascertaining whether there is a meaningful increased risk of suicidal ideation, suicide attempts, or suicide completion associated with any medication used to treat depression would require review of large numbers of patients. No suicide has ever been reported among the more than 4400 subjects enrolled in recent pediatric clinical trials of antidepressants.

As previously noted, the FDA’s review of a pediatric exclusivity supplement for paroxetine led to the finding that events suggestive of possible suicidality were contained, along with other events, under the term “emotional lability” in clinical trial adverse event reports.  To better examine potential causality between antidepressant use and suicidality, the FDA requested that the sponsor (Glaxo-Smith-Kline, GSK) review the adverse event reports and separate out verbatim terms suggestive of suicidality.  The sponsor performed such an analysis by electronically searching the adverse event data for certain events (terms) that might have represented suicidal behaviors, followed by a blinded review of these events to select those that appeared to be probably related to suicide. This analysis resulted in the submission of a report on paroxetine and pediatric suicidality, first to the MHRA, and shortly thereafter, to the FDA in May 2003.  This report suggested an increased risk of suicidality associated with paroxetine use.

Therefore, the FDA was concerned that adverse events related to suicidal behavior during the pediatric trials may not have been fully captured, correctly classified, and reported by sponsors in a standardized manner.  Starting in July 2003, the FDA’s Division of Neuropharmacological Drug Products (DNDP) sent a series of letters to various sponsors requesting more complete adverse event data and event narratives from pediatric trials including: (1) all adverse events suggestive of intentional self-injury, suicidal ideation, or suicide attempts;  (2) reports of accidental injuries and accidental overdoses; and (3) all reports of serious adverse events. Sponsors were asked to identify all events suggestive of suicidal ideation and/or self-injurious behavior using an FDA-specified search strategy and algorithm (Appendix 6; PDF, 134 KB). The request for data included placebo-controlled pediatric trials for MDD, OCD, generalized anxiety disorder, social anxiety/social phobia, and attention deficit hyperactivity disorder from 9 antidepressant drug development programs involving 8 sponsors.

Office of Drug Safety Analysis.  FDA staff from the Office of Drug Safety analyzed 22 short-term placebo-controlled trials involving 9 different antidepressant drugs using sponsor-identified suicide related events to estimate incidence rates for suicidality and person years of exposure.73  These trials included 4250 pediatric subjects, 2298 treated with active drug and 1952 treated with placebo. There were 108 patients with suicide-related events (74 on active drug and 34 on placebo); 78 of these adverse events were serious (54 on active drug and 24 on placebo).

Overall, comparing active drug treatment to placebo, there was an association of suicide-related events and serious suicide-related events with active drug treatment. This association was observed principally in MDD trials. For serious suicide-related events in MDD trials, the relative risk was 1.9 (95% confidence interval 1.2–3.2), and the attributable risk was approximately 0.085 events per patient-year of exposure to drug (p-value = 0.015), equivalent to approximately 1 excess serious suicide-related event per 12 person years of drug treatment. For non-MDD trials, the data also showed a higher rate of events with active drug treatment, but the attributable risk for serious events was much smaller than for MDD trials, and the data were not statistically significant.  Considering individual drugs separately, the data for venlafaxine and paroxetine showed a statistically significant increase in suicide-related events relative to placebo, while fluoxetine (0.9; [95% confidence limits 0.3-2.3]) and mirtazapine (0.5) had relative risks below 1.0. 

Columbia Review.  To facilitate analysis of varied pediatric studies, the FDA obtained adverse event narratives from sponsors and contracted with the Columbia Expert Suicidality Classification Board to review and reclassify the events. The Board is a joint collaboration of the Departments of Child Psychiatry and Neuroscience at Columbia University, comprised of experts in pediatric suicidality classification and research. The charge to Columbia was to perform an independent and blinded review of event narratives for: (1) adverse events categorized by various drug company sponsors as “possibly suicide-related”; (2) accidental injuries; (3) accidental overdoses; and (4) all other events categorized by sponsors as serious adverse events from pediatric antidepressant trials.  Because of the lack of systematic or standardized language used to define suicidal behavior in industry-sponsored antidepressant trials, and the difficulty in interpreting the meaning of reported adverse events that occurred in these trials, this project attempted to apply a common set of guidelines, so that data could be examined consistently (to the extent possible) across trials. 

The Columbia suicidality classification scale is shown in Appendix 7 (PDF, 134 KB).  The narratives were reviewed for adverse events that occurred during the randomized double-blind phase and/or within 30 days of the last dose of randomized treatment from 25 placebo-controlled antidepressant trials. These narratives included all events suggestive of intentional self-injury, suicidal ideation or suicide attempts, accidental injuries, accidental overdoses, and all reports of serious adverse events. The narratives were composed of sponsor summaries of information pertinent to these events obtained from case report forms and at times from other sources (eg, medical charts).

Ultimately, using a consensus-based process, events were classified as suicide attempts; suicidal preparatory actions or ideation; suicidal ideation behavior─intent unknown or as “unclassified” because of lack of sufficient information.  The experts were able to reach consensus on each event; approximately 10% of these classifications differed from the original sponsor classification.  A total of 423 events (including multiple events for some study participants) were independently rated and classified by this panel.  These results were submitted to the FDA and staff from the Division of Neuropharmacologic Drug Products (DNDP) conducted a meta- analysis. An internal FDA audit validated the reproducibility of the classification methodology.¹⁰¹

FDA Meta-analysis of Columbia Classified Data.  Overall, the DNDP meta-analysis included 24 trials conducted in pediatric patients in 9 drug development programs plus the TADS trial.102 Seventeen of these trials involved SSRIs (citalopram–2; fluoxetine–5; fluvoxamine–1; paroxetine–6; and sertraline–3).  Trials involving atypical antidepressants included bupropion–2; mirtazapine–1; nefazodone–2; and venlafaxine–4.  Based on indications, these trials involved MDD–16; OCD–5; generalized anxiety disorder–2; social anxiety disorder/social phobia–1) and attention deficit hyperactivity disorder–2.  In the TADS trial, harm-related events were defined as one or both of the following:  harm to self (non-suicidal, ideation, or attempt) or harm to others (requires ideation or attempt).  Suicide-related events were defined as harm to self (requires ideation or attempt) and suicide attempts.

With regard to the main outcome (Appendix 8; PDF, 134 KB), the FDA meta-analysis found that based on adverse event reports, suicidality (the combination of new suicide attempts, new onset suicidal ideation, and worsening of existing suicidal ideation), occurred in 3.8% of antidepressant recipients and 2.1% of placebo recipients.¹⁰²   When events indicative of suicidality from all the clinical trials were pooled, the rate of definite or possible suicidality among children assigned to receive antidepressants was twice that in the placebo group (summary risk ratio 2.19). These findings were not altered by the consideration of certain trial design attributes including exclusion of baseline suicide risk, suicide attempt, and homicidal risk. These values were somewhat lower, but still statistically significant when considering only the SSRI/MDD trials (Appendix 9; PDF, 134 KB).  Thus, both the Office of Drug Safety analysis of sponsor adverse event reports and the DNDP analysis using the Columbia University reclassification of cases indicate an association of suicidality with antidepressant drug treatment in short-term (8 to 12 weeks), placebo-controlled pediatric trials. 

Interestingly, 17 of the trials that were analyzed had information that was prospectively obtained from clinical trial subjects using the suicide-related query on standard rating instruments that were used to evaluate the severity of depression (eg, item 3 of the HAM-D scale).  These trials included the 15 MDD trials, as well as 2 additional trials on social anxiety disorder and OCD.  FDA meta-analysis of this information with respect to the emergence or worsening of suicidality found no link with antidepressant use.103   To the CSA’s knowledge, the relative importance of this finding has never been explained. Back to top

Other Safety Issues with SSRIs

SSRIs offer the advantage of having fewer anticholinergic effects, less sedation, less weight gain, and fewer cardiac effects than the TCAs.  In adults, side effects reported in association with the SSRIs include gastrointestinal difficulties (nausea, vomiting, diarrhea), central nervous system effects (agitation, extrapyramidal symptoms, hyperkinesias, disinhibition, jitteriness, headache, dizziness, insomnia [but sometimes somnolence or fatigue] and tremor), and sexual dysfunction; this pattern also occurs in children and adolescents.^65,104   Slowing of growth also has been reported.  The clinical use of SSRI antidepressants may be associated with discontinuation symptoms including dizziness, nausea, paresthesias, tremor, anxiety, and dysphoria.

SSRIs can be associated with other side effects that are potentially problematic including behavioral activation/disinhibition and induction of mania.^105-107  An increase in motor activity may be more common in children than adolescents or adults.^107,108  All antidepressants can induce  mania in patients with underlying bipolar disorder, and this effect is not unique to children and adolescents.  Clinical wisdom suggests that prepubertal children are particularly sensitive to the dose-dependent activating effects of SSRIs early in the course of treatment.  Whether or not such behavioral activation/disinhibition is related to suicidal ideation and/or increases the risk of self-injurious acts is not at all clear.  It has been suggested that activation/disinhibition might make a latent thought, feeling, or behavior more explicit—for example, an individual child with suicidal ideation may be more likely to describe the suicidal thought or to act on it when activated/disinhibited. Back to top

Summary and Comment

Children and adolescents deserve the same level of evidence that is required for adults to determine that therapies used are safe, effective, and properly dosed.  However, children and adolescents represent a heterogeneous group who undergo rapid metabolic, hormonal, physiologic, and developmental changes.  Over the last decade, the FDA has actively supported many efforts to encourage development of information on the appropriate use of prescription drugs in the pediatric population.  Evidence derived from clinical trials to support pediatric therapeutics, while improving, is still inadequate for many conditions, including pediatric MDD. 

Several clinical trials conducted on antidepressants in children and adolescents with MDD for the purpose of gaining additional marketing exclusivity failed to demonstrate efficacy.  Only fluoxetine has consistently demonstrated efficacy in pediatric MDD; combining it with CBT appears to be most helpful in adolescents. Failure to meet the FDA’s standard for approval in several of the pediatric antidepressant drug trials does not prove lack of benefit in pediatric MDD; however, failure to show benefit significantly heightens concern about the possibility of certain risks, in particular, induction of suicidality.  Further trials examining the relative benefit and risk of SSRIs in pediatric MDD may be best served by the use of innovative study designs such as  placebo-controlled trials of longer duration that include a randomized drug discontinuation phase, the use of a positive control arm (fluoxetine) to validate the ability of the study design to detect efficacy, and the use of approaches (eg, pharmacogenomics, compliance assays, etc.) to identify the subpopulations of pediatric patients that respond to medication and those that are at increased risk for developing serious adverse drug reactions.

Data linking antidepressants with an increased risk of suicidal behavior in children and adolescents emerged from the adverse event reports obtained from 24 completed pediatric antidepressant clinical trials (including TADS), most of which were conducted as part of an effort to gain additional marketing exclusivity.  The FDA’s detailed review of adverse event reports from placebo-controlled, short-term clinical trials of antidepressants in children and adolescents found that the use of antidepressants is associated with a doubling in the number of reports indicative of suicidal thinking and behavior in children and adolescents with MDD and other psychiatric disorders. No suicides were reported in these studies.  The subset of clinical trials on MDD generally attempted to exclude subjects with serious suicidal ideation or behavior;  however, the FDA’s analysis of trial design attributes including exclusion of baseline suicide risk and suicide attempts did not alter their findings.  On the other hand, the FDA’s meta-analysis of treatment emergent suicidality among study patients in MDD trials as measured by the suicidality item(s) in various depression questionnaires found no link between antidepressant medications as a class and the emergence or worsening of suicidality.

The finding by the FDA that antidepressant drugs were associated with increased suicidality in children and adolescents could be explained, in part, by the fact that treatment was associated with an increased rate of reporting of suicidal thoughts or attempts (ie, the drug may facilitate the communication of such events).  However, this hypothesis has not been tested and can only be verified by better ascertainment of suicidality than was used in any of the pediatric exclusivity trials. 

Most, but not all, data from ecological studies, forensic analysis, and drug discontinuation studies support the notion that the prescription of antidepressants, including SSRIs, reduces suicidal behavior and completed suicide attempts overall and in adolescents, although the risk of such behavior appears to be highest during the initial course of drug therapy.  The results obtained from patient-level controlled observational studies emanating from general practice are variable but found some evidence of an increased risk for suicide or suicidal behavior for SSRIs with respect to age or specific drug.  Data obtained from one study involving a managed care database were essentially neutral (neither protective nor harmful) with respect to the effect of antidepressants on the likelihood of a suicide attempt in adolescents with MDD.  In conclusion, a causal role for antidepressants in increasing suicides in children and adolescents has not been established.

The safety of antidepressants in children and adolescents is a relative concept to be examined in light of the severity of the disorder being treated and the anticipated benefits and risks of treatment.  Suicidal ideation is common in depressed adolescents, and up to one-third of these individuals may attempt suicide at some time. Thus, concerns that antidepressants potentiate suicidal or self-injurious behavior need to be balanced by the clear risk of suicide in children and adolescents with untreated depression.  There is a need for properly designed and powered pragmatic studies of antidepressants in children and adolescents that could test the concerns raised by the MHRA and FDA analyses.  Results from the TADS trial provide reassurance on the broader issue of treatment-emergent suicidal behavior in adolescents, although concerns about self-harm in fluoxetine recipients remain. 

Until these issues are resolved, “prudent practice in the treatment of depressive illnesses in children and adolescents must include careful attention to the decision to treat a child or adolescent with medication for MDD.”64  Depressed patients who are treated with antidepressants should be closely monitored for emergent suicidality, hostility, agitation, and mania.  Families and patients should be informed about the benefits and risks of these drugs and be re-educated about monitoring for emergent side effects and symptoms of mood instability

RECOMMENDATIONS

The following statements, recommended by the Council on Scientific Affairs, were adopted by the AMA House of  Delegates as AMA policy and directives at the 2005 AMA Annual Meeting:

The AMA:

1. Recommends that selective serotonin reuptake inhibitors (SSRIs) should remain available for use in children and adolescents, including unlabeled uses, subject to the exercise of prudent clinical judgment and development of clinical guidelines for treatment.  Current clinical evidence indicates that fluoxetine is an effective SSRI in children and adolescents with major depressive disorder. (Policy)
2. Urges the Food and Drug Administration (FDA) to ensure that studies conducted by sponsors in pursuit of pediatric exclusivity be adequately designed and of sufficient duration to answer clinically relevant efficacy and/or safety questions that have evolved in a particular therapeutic area. (Directive)
3. Recognizes that the current product labeling (package insert) of antidepressant drugs, including the Black Box warnings, is a precautionary statement intended to reinforce the need for careful monitoring of patients with depression and other psychiatric disorders during the initiation of treatment.  This product labeling should not be interpreted in a way that would decrease access for patients who may benefit from these drugs. (Policy)
4. Urges the FDA to evaluate the impact of labeling changes mandated by the Agency for antidepressants, including the Black Box warning and Patient Medication Guide on treatment patterns, patient compliance, and patient access. (Directive)

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