Where is the Scientific Evidence to Justify Exposing Children to the Risks of Antidepressant Drugs?

Alliance for Human Research Protection (AHRP)
Tel. 212-595-8974 Fax: 212-595-9086
142 West End Ave. Suite 28P, New York, NY 10023

Comments by Vera Hassner Sharav
President, The Alliance for Human Research Protection

Submitted to: FDA Advisory Committee Psychopharmacological Drugs Advisory Committee and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee February 2, 2004 Meeting RE: Suicidality Associated with Antidepressant Drug Treatment

These comments, submitted by the Alliance for Human Research Protection, will focus on documented evidence showing that published reports about pediatric antidepressant drug trials are not consistent with the unpublished data. We question the FDA’s failure to exercise its authority to warn physicians and the public about negative trial results and the potential for severe risks of harm, including drug-induced suicidal behavior. We present documented evidence to answer the following questions:

1. What does the clinical trial evidence demonstrate about the effectiveness of SSRIs in children?

In FDA’s January 5, 2004, background memorandum to the advisory committee, Dr. Thomas Laughren,[1] FDA’s Team Leader, Psychiatric Drug Products Division of Neuropharmacological Drug Products, acknowledges concern about “the preponderance of negative studies of antidepressants in pediatric populations.” Furthermore, Dr. Laughren acknowledges that even published journal reports claiming positive results in pediatric SSRI clinical trials proved to be negative. The memo cites the Keller[2] et al, published Paxil study which claimed to show positive results, but in fact failed on the primary endpoint. FDA’s memo also cites a report by Wagner[3] et al, which was published in the Journal of the American Medical Association (JAMA, 2003), claiming positive findings for Zoloft by pooling two studies. However, as FDA now acknowledges,1 when examined individually, the Wagner studies actually failed to demonstrate positive outcomes. In its January, 2004 memo FDA mentions: “Of note, the published literature gives a somewhat different perspective, suggesting more positivity [sic] than was the conclusion at FDA.”[1]

This disparity underscores a disturbing inconsistency between published and unpublished reports – raising concern about the integrity of peer-reviewed journal reports.

2. What was the scientific justification for FDA’s approval of Prozac for the treatment of children with depression?

On January 3, 2003, FDA approved Prozac as a treatment for the treatment of children with depression on the basis of a single published positive antidepressant treatment report – the 1997 Emslie,[4]et al study, conducted between April 1991 and February 1995. However, that study has been criticized for its flawed methodology[5] [6] [7]and weakness in demonstrating drug efficacy.[8] Emslie, et al, screened 583 patients enrolling 106 in the placebo washout period. Of these, 10 improved on placebo but were dropped from the study. The remaining 96 were randomized to fluoxetine (n=48) or placebo (n=48), of whom 37.5% dropped out before eight weeks.5 Complete symptom remission occurred in only 15 (31%) fluoxetine-treated children versus 11 (23%) on placebo – a mere 8.3% differential.

* FDA’s[9] own statistical analysis of the 1997 Emslie4 study found that the study failed to achieve the protocol specified endpoint – as did the Keller Paxil study. FDA’s statistical analysis report concludes: “…based on this primary endpoint (recovery defined as below 28 on the CDRS-R and a CGI of 1 or 2) from Dr. Emslie’s protocol, the result was not significant (p= 0.339)·.In conclusion, the sponsor did not win on the protocol specific endpoint (i.e. recovery rate) although the sponsor achieved minimal significance based on the post hoc endpoint……the result for acute treatment period was not significant (p= 0.093). So, based on the primary endpoint, there was no evidence of treatment effect.” (p. 37) Emslie et al, claimed in the published report: “side effects, as a reason for discontinuation, were minimal, affecting only 4 patients who were receiving fluoxetine·” (p. 1033). However, these 4 children represent 8.3% of the fluoxetine treated group, and they developed “manic symptoms” and “a severe rash.” These adverse effects are not considered “minimal.”

As noted in a recent editorial[10] and by the FDA, Center for Drug Evaluation and Research independent analysis, in the second Emslie study[11] (more than twice as large but positive results even less impressive), “fluoxetine failed on one of the two pre-determined outcomes and on the other measure, only 52% improved versus 37% on placebo.” Emslie’s claimed Îpositive’ findings were based solely on one out of five outcome measures: namely, clinicians’ rating of improvement, without regard for parents’ or client’s own assessment, which can differ substantially.[12] The study’s use of inactive placebo is likely to have compromised the study’s blind inasmuch as patients and staff recognize drug-induced side-effects. And the investigators’ (subsequently disclosed) financial ties to Eli Lilly, the manufacturer of the drug being tested raise serious concerns about the integrity of the study. When questioned by a New York Times reporter, Dr. Emslie acknowledged that: “Any relative difference in effectiveness between S.S.R.I.’s is probably best explained by methodological differences and not by specific differences in the medications.”[13] Given the weak efficacy findings from a flawed study, it is difficult to justify FDA’s approval of Prozac for the treatment of depression in children.

  • On December 18, 2003, Eli Lilly[14] issued letters to British healthcare professionals, indicating that fluoxetine (Prozac) is NOT recommended for children – for any use. No such warning was issued to US physicians.

3. What does the evidence show about SSRI-induced adverse effects in children?

A. Evidence from controlled clinical trials:

Evidence of a drug-induced mania, agitation, aggression, and suicidal behavior in some children who were prescribed SSRIs emerged more than a decade ago.

  • In 1991, King et al[15] reported that 6 of 42 children and adolescents (14%) with obsessive-compulsive disorder developed “intense self-injurious ideation and/or behavior” during a controlled trial of fluoxerine (Prozac). Case 1 focuses on a 12-year old boy whose violent reaction to the drug may provide insight into the school shootings years later by boys who were prescribed an SSRI. Although initially improved, 38 days after starting the trial, the boy had a violent nightmare about killing his classmates until he himself was shot. Upon waking the dream continued to feel “very real” and reported increasingly bad dreams with images of killing himself and of his parents dying. He became agitated and anxious, refused to go to school, and reported, “marked suicidal ideation that made him feel unsafe·” (p. 180) The blind was broken, and it was revealed he was taking fluoxetine. The boy was hospitalized for 3 days, and then re-hospitalized for a month when thoughts of self-harm persisted. Three weeks after the last hospitalization a physician who was not involved in the trial put the boy back on Prozac, and he again became suicidal. The case is particularly significant in demonstrating a causal effect of the drug[16] because:
    • It occurred within the context of a controlled clinical trial;
    • Violent symptoms developed with start of Prozac (challenge);
    • The symptoms ceased when the drug was stopped (dechalllenge);
    • Suicidal symptoms returned when the drug was restarted (rechallenge);
    • Suicidal symptoms cleared a second time when the drug was again stopped.

* In the 1990s Pfizer conducted several trials testing sertraline (Zoloft) in children (aged 6-12) and adolescents (aged 13-17) years. The children were diagnosed either with depression or obsessive-compulsive disorder (OCD). In a 12-week multi-center, double blind, placebo-controlled study, 92 children tested Zoloft and 95 were given placebo. Of those who completed the trial, 67 subsequently went onto Zoloft in an extension trial. A second 51-day open label study recruited 61 children (44 depressed and 17 with OCD) to look at the pharmacokinetics of and tolerance to sertraline after single and multiple doses. Three published reports concluded that Zoloft was “safe and effective.” March, Biederman,[17] et al, reported in the Journal of the American Medical Association: “Sertraline appears to be a safe and effective short-term treatment for children and adolescents with obsessive-compulsive disorder;” Alderman,Wolkow, [18] et al, reported in the Journal of the American Academy of Child & Adoldescent Psychiatry: “Sertraline can be safely administered to pediatric patients using the currently recommended adult titration schedule;” and Ambrosini, Wagner, [19] et al, reported in the same journal: “Sertraline was generally well tolerated and did not induce manic symptoms.” These claimed positive findings are inconsistent with the unpublished data.

FDA’s review of Pfizer’s sertraline (Zoloft) clinical trial database:

In March 1996, FDA reviewer, Dr. James Knudsen, raised concern about “an increased frequency of reports of suicidality in the pediatric/adolescent patients exposed to sertraline compared to either plaebo or sertraline-treated adult OCD patients.”[20] He requested a report from Pfizer about suicidal events in these pediatric trials.

On May 23, 1996, Pfizer complied.[21] On October 25, 1996, in a follow-up memo,[22] Dr. Thomas Laughren, notes that Dr.Knudsen’s review found: “[a] 7-fold greater incidence of suicidality in children taking sertraline compared to adults.” Specifically, an “incidence of suicidality for adults taking sertraline of 9 / 1581 (0.6%) compared to 1 / 426 (0.2%) for placebo patients. The comparable crude incidence data for pediatric patients were 6 / 220 (3.0%) for sertraline and 0 / 95 for placebo.”

In 1997, Pfizer submitted a second, amplified Expert Report[23] to the FDA. The data in these Pfizer reports show that not only were children in those trials subjected to increased suffering in trials designed to test the maximum tolerable, but children testing Zoloft were put at increased risk of self-injury, violent outbursts, and suicidal behavior. In these completed studies, 6 children on Zoloft attempted suicide and a number of others became suicidal. Among the 44 depressed children, 4 attempted suicide – a rate of 9%.

Suicide attempts in the main occurred within a few days of dose escalation. One of the six children who became suicidal was an eight-year-old boy who had been in the sertraline dose tolerance study for 36 days. Table 1 of the Pfizer 1996 suicides report states: “Patient was hospitalized for a suicide gesture, and dropped from the study. The patient #4 mutilated himself by cutting his feet with a razor blade and tying a tie around his neck. There was no previous history of self-mutilation or suicidality, although family history was significant for affective disorder (mother, maternal uncle) and suicide (maternal uncle).”21 Pfizer’s report acknowledges: “The event was attributed to study drug by the investigator.”

Pfizer (1996) reported 25 cases of “spontaneous reports of suicide-related behavior in children,” (p. 13) Prizer’s 1997 report refers to 21 severe adverse effects (SAEs) in 16 children (of 220) on Zoloft in the OCD studies. In the depression studies, Pfizer reports 11 SAE in 7 (of 38) children on Zoloft (18.4%): “These included three reports of suicidality, and single reports of malaise, intentional drug overdose, medical/ surgical·aggressive reaction, aggravated depression·”(p. 29) Pfizer’s 1997 report23 states: “The adverse events most frequently associated with discontinuation were psychiatric symptoms, most commonly agitation” (p. 21). Children on Zoloft were especially prone to agitation: 15.1% (compared to 1.9% on placebo); 10.3% of adolescents on Zoloft became agitated (compared to 2.4% on placebo) (p. 23). Pfizer noted: “there were no serious adverse events reported in the 95 patients in the placebo group”(p.28). It is significant that the report is based on “spontaneous” (i.e., voluntary) reports – the children and adolescents were not monitored for suicidal behavior.

Of note is the fact that in industry-controlled clinical trials suicidal subjects are always excluded. Yet, clinical trial evidence shows that children taking SSRIs have been shown consistently to be two to three times more likely than children on placebo to manifest suicidal ideation or behavior.[24]

  • In 1998, March, et al[25] reported that 37% of children treated with an SSRI suffered psychiatric adverse effects.
  • In 2001, Keller, et al,2 reported that 17% of children suffered adverse effects.
  • On June 10, 2003, the British authority issued a warning of a two-to three-fold increased risk of suicide in pediatric clinical trials testing SSRI.
  • On June 18, 2003, GlaxSmithKline [24] issued a warning to British physicians against the use of Paxil in children, acknowledging failure of clinical trials “to demonstrate efficacy in major depressive disorders and doubling the rate of reported adverse events – including suicidal thoughts and suicide attempts – compared to placebo.”
  • On August 22, 2003, Wyeth24 Pharmaceuticals followed suit and issued a letter of warning to UK and US healthcare professionals: “In pediatric clinical trials, there were increased reports of hostility and especially in Major Depressive Disorder, suicide-related adverse events such as suicidal ideation and self-harm.”
  • On December 18, 2003, Eli Lilly[26] issued two letters to British healthcare professionals, indicating that fluoxetine (Prozac) is NOT recommended for either premenstrual dysphoric disorder (PMDD) or for children – for any use.

B. Evidence of harm from clinical care centers:

  • A systematic two year review of the medical records of 82 children and adolescents treated with an SSRI antidepressant at Massachusetts General for depressive or obsessive-compulsive disorders was conducted by Harvard University child psychiatrists, Wilens, Biederman, et al.[27] The investigators, who have long advocated prescribing psychotropic drugs for children, reported in 2003 that:
    • 22% of children suffered drug-induced psychiatric adverse effects (PAE), “most commonly related to disturbances in mood” within three months of treatment with an SSRI.
    • “Overall, 74% of children and adolescents experienced [i.e., suffered] an adverse event to an SSRI over the course of their treatment.”
    • Underscoring the fact that these PAEs were drug-induced, the investigators reported: “Re-exposure to an SSRI resulted in another PAE in 44% (n=18) of the group.”

The authors note that these findings from their naturalistic sample of children & adolescents and mirror the reports of carefully screened, controlled clinical trials of SSRIs for OCD and depression. Willens, et al conclude: “Our data combined with the literature suggest that sleep disturbance and agitation are among the most common PAEs associated with SSRIs.” Sleep disturbance and agitation are chief signs of bipolar disorder, leading one to question whether in routine clinical practice such drug-induced adverse effects might be mistakenly viewed as psychiatric disorders, resulting in further (and inappropriate) psychotropic drug treatment.[28] [29] Clinicians have noted that children are increasingly being diagnosed with bipolar disorder,[30] a previously rare condition in children.

  • A 1995 report by Tierney, et al[31]found that 21% of children experienced behavioral adverse events on SSRIs.
  • A 1991, study by Riddle, et al,[32] found that 50% of children treated with Prozac (20-40 mg) for depression or OCD suffered adverse effects.
  • An earlier chart review of efficacy and adverse drug reactions by Dr. Jain, [33] University of Pittsburgh, found that 23% of children (8 to 18) who were prescribed Prozac suffered mania or manic symptoms and another 19% became hostile and aggressive, exhibited grinding anger, short tempers.
  • A 2001 retrospective review of 533 psychiatric hospital admissions over a 14 month period found that 8.1% were admitted due to antidepressant-induced mania or psychosis.[34] In 70% of those admissions, SSRIs induced these extreme symptoms.
  • Since the increased use of psychotropic drugs, physicians have observed that children are increasingly being admitted to psychiatric hospitals.[35]
  • An investigative report, “Medications Can Fan Children’s Emotional Flames,” in the Tampa (Florida) Tribune[36]examined 600 sheriff’s reports, revealing that the psychotropic drugs prescribed for children triggered hostility, aggression, and threats of suicide, which landed them in crisis units.

4. Why did the FDA fail to inform physicians and the public that “the preponderance” of pediatric clinical trials of antidepressants were negative, that they failed to show a benefit greater than placebo in children?

FDA’s mission and responsibility is “protecting the public health by assuring the safety and efficacy·of drugs· advancing the public health by helping to speed innovations that make medicines [sic] more effective, safer and more affordable; and helping the public get the accurate, science-based information they need to use medicines [sic] to improve their health.” [37] The public expects the FDA to lend its seal of approval only for drugs that have passed rigorous scientific standards, and have proven their efficacy and safety, demonstrating a favorable risk/ benefit ratio. FDA is responsible for providing the public with “accurate, science-based information” about the proven /unproven benefits and evidence of potential risks. FDA officials have noted – but failed to inform the public – that SSRIS have failed to show they are effective for treating depressed children.1 If FDA approves drugs whose risk / benefit ratio is in dispute, the agency has a duty to inform physicians and the public about insufficient efficacy and the attendant risks. FDA has the authority to require that such drugs carry prominent warnings in the label.

5. Why did FDA fail to warn physicians and the public about the risks for children taking an SSRI – including a two-to three-fold increased risk of suicidal behavior?24

As demonstrated above, FDA officials have known for years that a body of evidence exists – from both clinical trials and clinical practice – showing that children prescribed an SSRI are at increased risk of suffering severe drug-induced adverse effects – including a two-to-three fold increased risk of suicidal acts. FDA’s failure to warn about the risks, coupled with its failure to prohibit drug companies from making false claims in advertisements, has encouraged drug companies to promulgate unsubstantiated pronouncements about the safety and efficacy of SSRIs in direct advertising and even in the scientific literature. For example, Brent and Birmaher[38] (2002) made the following unsubstantiated assertion: in The New England Journal of Medicine: “SSRIs are the most commonly used treatment for adolescent depression, because of the proven efficacy of fluoxetine, citalopram, and paroxetine in placebo-controlled trials, with a response rate of approximately 60 percent and a favorable side-effect profile” (p. 668). Such incorrect, incomplete, and misleading pronouncements have, no doubt, resulted in the spiraling increased use of psychotropic drugs in children and adolescents in the US.[39] [40] [41] [42] [43]

The greatest percentage increase of psychotropic drug use for children (between 1995 – 1999) was for SSRIs (62%), which increased from 7.9 per 1000 in 1995 to 12.8 per thousand in 1999. If these widely prescribed drugs are not beneficial, and for some children, they pose life-threatening risks, how can the FDA justify its failure to warn?

[1] U.S. Food and Drug Administration (FDA) CDER. Memorandum from Thomas P. Laughren, MD, to Members of PDAC and Peds AC January 5, 2004.

[2] Keller MB, Ryan ND, Strober M, Klein RG, Kutcher SP, Birmaher B, Hagino OR, Koplewicz H, Carlson GA, Clarke GN, Emslie GJ, Feinberg D, Geller B, Kusumakar V, Papatheodorou G, Sack WH, Sweeney M, Wagner KD, Weller EB, Winters NC, Oakes R, McCafferty JP. Efficacy of paroxetine in the treatment of adolescent major depression: A randomized, controlled trial. Journal of the American Academy of Child & Adolescent Psychiatry, 2001, 40:762-772.

[3] Wagner KD, MD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, Childress A, Donnelly C, Deas D, for the Sertraline Pediatric Depression Study Group . Efficacy of Sertraline in the Treatment of Children and Adolescents With Major Depressive Disorder. JAMA. 2003. 290:1033-1041

[4] Emslie, G.J., Rush, A.J., Weinberg, W.A., Kowatch, R.A., Hughes, C.W., Carmody, T., Rintelmann, J. (1997). A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Archives of General Psychiatry, 54(11), 1031-1037.

[5] Cohen DC. Clinical psychopharmacology trials: “Gold Standard” or fool’s gold? In Kirk, S. (Ed). (in press). Mental disorders in the social environment: Critical perspectives. New York: Columbia University Press.

[6] Duncan, B., Miller, S., Sparks, J. (in press). The heroic client: Becoming client directed and outcome informed (2nd edition). San Francisco: Jossey Bass.

[7] Sparks, J., & Duncan, B. (in press). The ethics and science of medicating children. Ethical Human Sciences and Services.

[8] Garland J. Facint the evidence: antidepressant treatments in children and adolescents. In press. Canadian Medical Association Journal.

[9] FDA. CDER. Application 18-936 / SE 5-064 (Eli Lilly, fluoxetine, Prozac). Statistical Analysis. Online at: http://www.fda.gov/cder/foi/nda/2003/18936S064_Prozac%20Pulvules_statr.pdf .

[10] Varley, CK, 2003. Editorial Psychopharmacological Treatment of Major Depressive Disorder in Children and Adolescents, JAMA, 290: 1091-1093.

[11] Emslie GJ, Heligenstein JH, Wagner KD, Hoog SL, Ernest DE, Brown E et al. 2002. Fluoxetine for acute treatment in children and adolescents: a placebo-controlled randomized clinical trial. Journal of the American Academy of Child & Adolescent Psychiatry, 41:1205-1215.

[12] Greenberg, R.P., Bornstein, R.F., Greenberg, M.D., & Fisher, S. (1992). A meta-analysis of antidepressant outcome under “blinder” conditions. Journal of Consulting and Clinical Psychology, 60, 664-669 and Greenberg, R.P. & Fisher, S. (1997). Mood-mending medicines: Probing drug, psychotherapy, and placebo solutions. In S. Fisher & R.P. Greenberg (Eds.), From Placebo to panacea: Putting psychiatric drugs to the test (pp. 115-172). New York: Wiley.

[13] Goode E. British ignite a debate on drugs and suicide. The New York Times, December 16, 2003, p. F-1.

[14] Eli Lilly. Letter to UK Healthcare Professionals, December 18, 2003. Online at: https://ahrp.org/risks/ProzacKids1203.php

[15] King RA, Riddle MA, Chappell PB, Hardin MT, Anderson GM, Lombroso P, Scahill L. Emergence of self-destructive phenomena in children and adolescents during fluoxetine treatment. Journal of American Academy of Child & Adolescent Psychiatry. 1991.30: 179-86.

[16] Breggin PR. Suicidality, violence and mania caused by selective serotonin reuptake inhibitors

(SSRIs): A review and analysis. International Journal of Risk & Safety in Medicine. 2003/2004. 16: 31- 49

[17] March JS, Biederman J, Wolkow R, Safferman A, Mardekian J, Cook EH, Cutler NR, Dominguez R, Ferguson J, Muller B, Riesenberg R, Rosthenal M, Salee FR, and Wagner KD. 1998. Sertraline in Children and Adolescents With Obsessive-Compulsive Disorder Journal of the American Medical Association. 280:1752-1756.

[18] Alderman J, Wolkow R, Chung M, Johnston HF.1998. Sertraline treatment of children and adolescents with obsessive-compulsive disorder or depression: pharmacokinetics, tolerability, and efficacy. Journal of the Association of American Child & Adolescent Psychiatry, 37:386-94.

[19] Ambrosini PJ, Wagner KD, Biederman J, Glick I, Tan C, Elia J, Hebler JR, Rabinovich H, Lock J, and Geller D. 1999. Multicenter opin-label sertraline study in adolescent outpatients with major depression. Journal Of The Association Of American Child & Adolescent Psychiatry. 38:566-72

[20] Food and Drug Administration (FDA). 1996. Letter from James Knudsen, MD, PhD, reviewer of Zoloft pediatric safety data to Pfizer. March 19. Available under Freedom of Information Act.

[21] Pfizer. Safety Evaluation and Epidemiology. Suicide-related behavior in children and adolescents in the sertraline OCD clinical development program. Report submitted to the FDA. May 23, 1996. 25 pp. Available under the Freedom of Information Act.

[22] FDA. 1996. Memo marked “Confidential” from Dr. Thomas Laughren commented on data in the OCD database pertinent to the emergence of suicidal ideation, gestures, and attempts in association with sertraline use. October 25.

[23] Pfizer. Expert Report on the clinical documentation of sertraline hydrochloride for obsessive compulsive disorder in paediatric patients. Submitted to the FDA. Approved October 20, 1997. Available under the Freedom of Information Act.

[24] UK Medicines and Healthcare Products Regulatory Agency (MHRA). June 10, 2003.SEROXAT ban FOR TREATMENT OF CHILDREN WITH DEPRESSION http://www.info.doh.gov.uk/doh/intpress.nsf/page/2003-0223?OpenDocument ; GlaxoSmithKline. June 18, 2003. Dear Doctor (UK) Warning against using Paroxetine in children under 18, cites severe adverse effects during clinical trials occured at least twice as often as in placebo. https://ahrp.org/risks/PaxilRisks0603.php ; Wyeth. September 2, 2003. Dear Doctor warning against using Effexor in children under 18, cites clinical trial results: children who tested Effexor experienced: 2% rate of suicidal ideation – 0 for those on placebo.; 2% hostility – <1% for those on placebo. https://ahrp.org/risks/effexorLtr082203.php ; UK MHRA Advisory banning use of Efflexor in children under 18. Sept 19, 2003: http://www.info.doh.gov.uk/doh/intpress.nsf/page/2003-0350?OpenDocument ; U.K. MHRA. On Dec 10, 2003, completed its review of the pediatric antidepressant clinical trial data and issued a ban on prescribing all SSRIs but Prozac in children under 18.Online at: http://www.info.doh.gov.uk/doh/intpress.nsf/page/2003-0505?OpenDocument

[25] March J, Biederman J, Wolkow R, Safferman A, Sallee F, Ambrosini P, Cook E. Sertraline in children and adolescents with obsessive-compulsive disorder: A multicenter randomized controlled trial. Journal of the American Medical Association, 1998, 280:1752-1756.

[26] Eli Lilly. Letter to UK Healthcare Professionals, December 18, 2003. Online at: https://ahrp.org/risks/ProzacKids1203.php

[27] Wilens TE, Biederman J, Timothy E, Kwon A, Chase R, Greenberg L, Mick E, Spencer TJ. “Systematic Chart Review of the Nature of Psychiatric Adverse Events in Children and Adolescents Treated with Selective Serotonin Reuptake Inhibitors,” Journal of Child and Adolescent Psychopharmacology, 2003, 13: 143 – 152

[28] Craney J, Geller B. Clinical implications of antidepressant and stimulant use on switching from depression to mania in children. Journal of Child & Adolescent Psychopharmacology, 2003, 13(2):201-204.

[29] Sarampote CS, Efron LA, Robb AS et al. (2002). Can stimulant rebound mimic pediatric bipolar disorder? J of Child & Adolescent Psychopharmacology, 12(1):63-67.

[30] Geller B, Sun K, Zimerman B, Luby J, Frazier J, Williams M. Complex and Rapid Cycling in Bipolar Children and Adolescents: A Preliminary Study. Journal of Affective Disorders, 34 (1995): 259-268. See also, Papolos D, and Papolos J. Overcoming Depression, 3rd ed. New York: Harpercollins, 1997 and Papolos, Demitri, and Papolos Janice. The Bipolar Child. New York: Broadway Books, 1999, and Papolos D and Papolos J. Mood Stabilizers The Bipolar Child Newsletter March, 2000 Vol. 3

[31] Tierney E, Joshi PT, Llinas JF, Rosenberg LA, Riddle MA. Sertraline for major depression in children and adolescents: preliminary clinical experience. Journal of child & Adolescent Psychopharmacology, 1995, 5:13-27.

[32] Riddle MA, King RA, Hardin MT, Scahill L, Ort SI, Chappell P, Ramusson A, Leckman JF. Behavioral side effects of fluoxetine in children and adolescents. Journal of Child & Adolescent Psychopharmacology, 1991, 1:193-198.

[33] Jain J. Fluoxetine in child and adolescents with mood disorders: a chart review of efficacy and adverse reactions. Journal of Child & Adolescent Psychopharmacology. 1992, 2: 259-265.

[34] Preda A, Maclein R, Mazure C, Bowers M. Anti-depressant associated mania and psychosis resulting in psychiatric admissions. Journal of Clinical Psychiatry, 2001. 62:30-33

[35] “Hospitals have launched marketing campaigns to let the public know of the availability of these new or expanded facilities and services.” American Psychiatric Association. Position Statement: Psychiatric Hospitalization of Children and Adolescents. APA Document Reference No. 890004. Online at: http://www.psych.org/edu/other_res/lib_archives/archives/890004.pdf

[36] Peterson L. Medications Can Fan Children’s Emotional Flames

The Tampa Tribune, Apr 8, 2003. Online at: http://www.tampatrib.com/MGA7XB3B9ED.html

[37] FDA Mission Statement. Online at: http://www.fda.gov/opacom/morechoices/mission.html

[38] Brent, D.A., & Birmaher, B. (2002). Adolescent Depression. The New England Journal of Medicine, 347, 667-671.

[39] Safer DJ. Changing patterns of psychotropic medications prescribed by child psychiatrists in the 1990s. J Child Adolescent Psychopharmacoogyl. 1997. 7:267-274; Zito JM, Safer DJ, dosReis S, Gardner JF, Magder L, Soeken K, Boles M, Lynch F, Riddle MA. Psychotropic Practice Patterns for Youth A 10-Year Perspective, Archives of Pediatric and Adolescent Medicine, 2003. 157:17-25.

[40] Summary, Evidence Report/Technology Assessment Number 7:Treatment of Depression – Newer Pharmacotherapies. Rockville, Md: Agency for Health Care Policy and Research; March 1999. Available at: http://www.ahcpr.gov/clinic/deprsumm.htm

[41] Olfson M, Marcus SC, Weissman MM, and Jensen JS. National trends in the use of psychotropic medications by children. Journal of the American Academy of Child and Adolescent Psychiatry. 2002. 41:514-521

[42] Shatin D and Drinkard C. Ambulatory use of psychotropics by employer-insured children and adolescentsin a national Managed Care organization. Ambulatory Pediatrics, 2002, 2: 111-119.

[43] Zito JM, Safer DJ, DosReis S, Gardner JF, Magder L, Soeken K, Boles M, Lynch F, Riddle MA. Trends in the prescribing of psychotropic medications to preschoolers. Journal of the American Medical Association 2000, 283:1025-1030.

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