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This is the summary text of a presentation at the Vatican addressing: "The Question of the Use of Pharmaceuticals in Pediatrics." This presentation covers the clinical trial evidence and offers prescription guidelines

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  1. 1. Duncan, B. (2010). The question of the use of psychiatric pharmaceuticals in pediatrics.Proceedings of the XXV Annual International Conference of the Pontifical Council forHealth Care Workers, “Toward an Equitable and Human Health Care.” November,Vatican City. THE QUESTION OF THE USE OF PSYCHIATRIC PHARMACEUTICALS IN PEDIATRICS A 2004 US review concluded that spending for medications for childhood behaviorproblems now eclipsed expenditure for any other drug category, including antibiotics (MedcoHealth Solutions, Inc.). While the US continues to lead the world in psychiatric prescriptions toyouth, global use of ADHD drugs has increased by 274% (Scheffler et al., 2007) as prescriptionsfor antipsychotics doubled across Europe (e.g., the UK: Rani, Murray, Byrne, & Wong, 2008;and Germany: Schubert & Lehmkuhl, 2009). The number of youth taking 1 or more psychiatricmedicines has hit nearly 9% in the US, 6% in the UK, and 3% in Australia—although not oneclinical trial has examined polypharmaceutical intervention with children (dosReis et al., 2005). Prescriptions for antidepressants for youth have increased at a rate of 11% per year from1994 to 2000, and 5% per year since, totaling to over 11 million prescriptions written annually.The number taking antipsychotics soared 73% in the four years ending in 2005—over 2.5 millionyouth per year are prescribed antipsychotics (dosReis et al., 2005). A study of 11,700 USchildren under age 18 covered by Medicaid (program for the poor) found that the number ofchildren newly treated with antipsychotics increased from 1,482 in 2001 to 3,110 (or 26%) in2005 (Pathak, West, Martin, Helm, & Henderson, 2010). Another study found that childrencovered by Medicaid were prescribed antipsychotics at a rate four times higher than childrenwith private insurance, and were more likely to receive antipsychotics for unapproved uses(Crystal, Olfson, Huang, & Gerard, 2010). A study of foster care children (on Medicaid) foundthat 57% received three or more drugs (Zito et al., 2008), six times the national average. Finally,the use of antipsychotics with privately insured children, aged 2 through 5, has doubled between1999 and 2007 (Ofson, Crystal, Huang, & Gerhard, 2010). About 1.5% of all privately insuredchildren between the ages of 2 and 5, or one in 70, received some type of psychiatric drug in2007 despite the fact that there is little to no evidence in this age group.
  2. 2. 2 While psychotropic drug use has risen, community behavioral intervention has remainedflat or declined (Case, Olfson, Marcus, & Seigel, 2007). Several questions arise: First, are theskyrocketing rates of prescription justified by clinical trial evidence? Are physicians whoroutinely prescribe psychotropic medications following the scientific mandates of evidence basedmedicine (EBM)—the integration of the best research evidence with clinical expertise, includingpatient values, to make informed decisions about individual cases (Sackett, Rosenberg, Gray,Haynes, & Richardson, 1996)? Next, are children, by virtue of their powerless position anddependence on adults, the unwilling victims of an industry motivated by greed rather than socialconsciousness? Finally, are the differential rates of prescription of psychiatric drugs to poorchildren a violation of equitable and human health care? This presentation addresses thesequestions via a risk/benefit analysis of the major drug classes and provides a template for healthand pastoral professionals to evaluate the drug literature and facilitate medication decisions. Children and Antidepressants Two randomized controlled trials of fluoxetine (Prozac) (Emslie et al., 1997; Emslie etal., 2002) gained approval for young people aged 8-17 diagnosed with depression (FDA, 2003,January 3). However, both Emslie studies failed to find a statistical difference between Prozacand placebo on primary outcome measures. Additionally, in both trials, manic reactions andsuicidality were notably higher in the drug group compared with placebo (Sparks & Duncan,2008). An independent analysis by the FDA concluded that only 3 out of 15 published andunpublished trials of SSRIs showed them to be more effective than placebo on primary measures(Laughren, 2004). None of the 15 found differences on patient or parent rated measures. The NIMH funded Treatment of Adolescent Depression Study (TADS) (TADS Team,2004), again evaluated Prozac for the youth age group. TADS compared the efficacy of fourtreatment conditions: Prozac alone, cognitive behavioral therapy (CBT) alone, CBT plus Prozac,and placebo. Despite media claims, (The New York Times front page headline, “AntidepressantSeen as Effective in Treatment of Adolescents,” Harris, 2004), the FDA did not count TADS as apositive study for SSRIs due to the negative findings on its primary outcome measure. Otherend-point comparisons in TADS favored the combined medication/CBT arm. However,treatment was unblind, and only the combined group received all intervention components (drug,psychotherapy, psychoeducation and family therapy, and supportive pharmacotherapymonitoring), creating a significant disparity in favor of the combination arm. The TADS
  3. 3. 3recorded 6 suicide attempts by Prozac takers compared to 1 by non-Prozac takers, with morethan double the incidence of harmful behavior in the Prozac conditions compared to placebogroups (despite the exclusion of youths deemed at high risk for suicidal behavior). Nevertheless,the authors recommended that “medical management of MDD with fluoxetine, including carefulmonitoring for adverse events, should be made widely available, not discouraged” (p. 819)--achallengeable conclusion given its inconsistency with the study’s own harm data. In the 36-weekfollow up study (The TADS Team, 2007), all treatment conditions converged by 30 weeks withsignificantly more suicidal ideation in the Prozac alone group. The percentage of suicidal eventsfor those on Prozac was nearly 12%, double the 6% in the CBT group. The risks noted in published and unpublished data prompted the FDA to issue a blackbox warning on all antidepressants for youth for increased risk of suicidality and clinicalworsening (FDA, October, 15, 2004). Further support of the warning emerged from an analysisof placebo-controlled trials of nine antidepressants, a total of 24 trials involving over 4,400children and adolescents (Hammad, Laughren, & Racoosin, 2006). The investigation revealed anaverage risk of suicidality of 4% in drug treated youth, twice the 2% placebo risk. Children and StimulantsThe American Psychological Association (APA) Report of the Working Group on PsychoactiveMedications for Children and Adolescents (hereafter Working Group) (Working Group, 2006)noted the lack of data supporting long term efficacy or safety. Further highlighted was thatstimulants, while reducing symptoms, show minimal efficacy in general life domains of thechild, including social and academic success. Stimulant advocates, however, point to theMultimodal Treatment Study of Children with ADHD (MTA) (MTA Cooperative Group, 1999).Only 3 of 19 measures, all un-blinded, found differences favoring methylphenidate (Ritalin).Neither blinded classroom observers, the children themselves, nor their peers found medicationbetter than behavioral interventions. Moreover, 14-month endpoint assessments compared thoseactively medicated and those who had ended therapy (4 to 6 months after the last, face-to-face,therapeutic contact) (Pelham, 1999). Given this unfair comparison, the fact only 3 un-blindedmeasures found an advantage for Ritalin is telling. At the same time, 64% of MTA children werereported to have adverse drug reactions: 11% rated as moderate and 3%, severe. At 36 months,treatment groups did not differ significantly on any measure (Jensen et al., 2007). Decreases ingrowth in medicated children averaged 2.0 cm and 2.7 kg less than not medicated groups,
  4. 4. 4without evidence of growth rebound at 3 years (Swanson et al., 2007). In March of 2006, a safety advisory committee of the FDA urged stronger warnings onADHD drugs, citing reports of serious cardiac risks, psychosis or mania, and suicidality. TheFDA elected to forgo a black box warning for most ADHD drugs, choosing instead to highlightrisks on the label and include information with each prescription. Children and Antipsychotics The APA Working Group found that studies supporting the use of antipsychotics to treatchildren were plagued with methodological limitations. Consider the NIMH funded Treatment ofEarly Onset Schizophrenia Spectrum Disorders (TEOSS) (Sikich et al., 2008). TEOSS sought toexamine the efficacy, tolerability, and safety of two second generation antipsychotics (SGA)(risperidone or Risperdal and olanzapine or Zyprexa) for youths diagnosed with early-onsetschizophrenia spectrum disorder and to compare these to a first generation antipsychotic (FGA)(molindone or Moban). At the end of eight weeks, the response rate was 50% for those treatedwith Moban, 46% for Risperdal, and 34% for Zyprexa. Participants in the study were allowedconcomitant use of antidepressants, anticonvulsants, and benzodiazepines, compromising eventhese disappointing findings. A 17-year old boy committed suicide and an unspecified number ofparticipants were hospitalized due to suicidality or worsening psychosis. These events areparticularly disturbing in light of the fact that youths considered at risk for suicide were excludedfrom the study. Weight gain was deemed serious enough to warrant suspension of the Zyprexaarm. Adverse events were “frequent” in all three groups. Only those youth who “responded”during the initial eight weeks—54 of the 116—were entered into the 44-week maintenance study(Findling et al., 2010). Forty of the 54 youth dropped out during this period because of “adverseeffects” or “inadequate response.” Thus, only 14 of the 116 youth who entered the studyresponded to the medication and stayed on it for as long as one year—only 12%. A Critical Flaws Analysis The former editor of the New England Journal of Medicine called attention to theproblem of “ubiquitous and manifold . . . financial associations” authors of drug trials had to thecompanies whose drugs were being studied (Angell, 2000, p. 1516). Given the infiltration ofindustry influence, discerning good science from good marketing requires a willingness toengage primary source material, and a critical flaws analysis.Flaw # 1: Compromises to the Blind
  5. 5. 5 Fisher and Greenberg (1997) assert that the validity of studies, in which a placebo iscompared to an active medication, depends upon the “blindness” of participants who rate theoutcomes. They note that inert sugar pills, or inactive placebos, do not produce the standard sideeffect profile of actual drugs—dry mouth, weight loss or gain, dizziness, headache, nausea,insomnia and so on. Since study participants must be informed of the possibility and nature ofside effects in giving consent, they are necessarily alert for these events, enabling them tocorrectly identify their study group. In addition, interviews that listen for or elicit side effectinformation easily reveal active versus inactive pill takers, effectively un-blinding the study forclinical raters and skewing results. Moreover, many trial participants in placebo groups havepreviously been on drug regimens, even some just prior to entering the trial, and are thereforefamiliar with medication effects. All of the studies described above used inactive placebos ornone at all.Flaw # 2: Reliance on Clinician Measures In the Emslie studies, the MTA, and TADS, client-rated measures found no differencebetween the placebo and SSRIs and among the conditions in the MTA. The lack of endorsementof efficacy by clients in clinical trials begs the question: If clients don’t notice improvements,how significant can those rated by others be? In addition, clinician-rated scales are oftencategorical, allowing a subjective range of responses to participant interviews and potential biasdue to compromised blind conditions. Moreover, continuous data are often converted intodiscrete categories (e.g., response and non-response), further magnifying differences (Kirsch etal., 2002). Finally, some clinician-rated measures tilt toward specific domains of discomfort thatfavor the investigative drug, potentially distorting findings. For example, measures inantipsychotic trials, like TEOSS, favor medications with sedative properties and many trials addsedatives or use drugs with sedative effects (Moncrieff, 2001).Flaw # 3: Time of Measurement Psychiatric drugs are often prescribed for long periods of time. This suggests that mostclinical trials, which last for 6 to 8 weeks, are not measuring how well the drugs do in actualsettings. Additionally, differences between medication and other treatments or placebo groupsoften dissolve over time (Fisher & Greenberg, 1997). Without longer term follow-ups,conclusions about effectiveness in real life cannot be determined. Authors of many short-termclinical trials fail to discuss time-frame limitations or to modify accordingly claims made in
  6. 6. 6conclusions. For example, Emslie et al. (1997), an 8-week study, concluded that “fluoxetine in20 mg/d is safe and effective in children and adolescents,” (p. 1036) without mention of time.The MTA, TADS, and other studies show that differences with non-drug treatments tend todissipate over time, and that initial effects of drug treatment must be weighed in terms of longterm tolerability and impact beyond symptom remission. The TEOSS one year follow-up of only12% showing benefit offers a dramatic example.Flaw # 4: Conflicts of Interest Richard Smith, who resigned as editor-in-chief of the British Medical Journal because oframpant industry influence in academic research, explains that the number one aim of industry-sponsored trials is to find favorable results for the company drug (Smith, 2003). Most academicjournals now recommend transparency regarding funding sources and author affiliations. Withthese as caveats, readers can approach the study with a warranted skepticism and a more carefulanalysis of trial methods and conclusions. The 1997 Emslie et al. study, published prior todisclosure requirements, did not identify author affiliations. Emslie et al.’s second fluoxetine trialfor child and adolescent depression (Emslie et al., 2002) lists author affiliations on the first page.Here, readers learn that Emslie and Wagner are paid consultants for Eli Lilly, who funded theresearch and whose product was being investigated. The remaining six authors are listed asemployees of Eli Lilly and “may own stock in that company” (p. 1205).Flaw # 5: Minimization of Risks Many psychiatric drug studies downplay or fail to assess adverse drug reactions. As aresult, rates of side effects may be substantially under-reported (Safer, 2002). Instead of detailedtables, adverse events may be described in a narrative rather than tabulated formats (e.g., Emslieet al., 1997). Authors of trials often confidently assert that the drug is safe when the data, in fact,show otherwise. In a study of Risperdal with youth diagnosed with disruptive behavior disorders(Reyes et al., 2006), the literature review asserts that “Risperidone has consistently demonstratedefficacy and safety in both controlled short-term and open-label long-term studies” (p. 402). Fivestudies are cited to back this claim—two short-term (Aman, De Smedt, Derivan, Lyons, &Findling, 2002; Snyder et al., 2002) and three, longer-term (Croonenberghs, Fegert, Findling, DeSmedt, & Van Dongen, 2005; Findling, Aman, Eerdekens, Derivan, & Lyons, 2004; Turgay,Binder, Snyder, & Fisman, 2002). The two short-term trials showed significant differences between the Risperdal and
  7. 7. 7placebo groups for key adverse events: somnolence, elevated serum prolactin (for boys), andweight increase. The three longer-term studies were open-label extensions of the shorter termtrials and examined the long-term efficacy and safety of Risperdal in children ages 5 to 12 withlower than average IQ scores. In all three trials, the top reported adverse event was somnolence,ranging from 20.6% to 51.9%. Weight gain was another frequently reported problem (from17.3% to 36.4%). The pattern of increased prolactin levels was observed across the three trials.Five participants in Croonenberghs et al.’s study required antiparkinsonan medications, sixwithdrew due to EPS, and two developed tardive dyskinesia, while 26% of participants in Turgayet al. experienced EPSs. Overall, 76 of the 77 participants in Turgay et al. reported adverseevents, close to 92% in Croonenberghs et al., and nearly 91% in Findling et al. Yet, the authors of all 5 studies report the drug’s safety: “generally safe” and “welltolerated” are found in every abstract and conclusions section for all the studies. The claim that“risperidone has consistently demonstrated efficacy and safety” (p. 402), with the five studiesreviewed here as evidence is, at best, misleading, and at worst a rhetorical construction revealedonly via examination of the data. The problems of sedation, weight gain, increased serumprolactin, and movement disorders have been effectively swept under the rug, and the efficacyand safety case, over time, becomes undisputed (Sparks, Duncan, Cohen, & Antonuccio, 2010). Conclusions and Recommendations The clinical trial evidence does not justify current prescribing practices and isantithetical to evidence based medicine. While pharmacotherapy involves considerable risk foryoung people, psychosocial interventions have a strong track record with virtually no adverseassociated medical events, leading the Working Group (2006) to conclude their massive reviewwith the recommendation: “Thus, it is our recommendation that in most cases, psychosocialinterventions be considered first.” (p. 16.) This conclusion, however, does not eliminate medication as one choice among many butrather frees health and pastoral professionals to put other options on the table and draw in thevoices of those they serve: to engage in a risk/benefit discussion and help families choosetreatments in concert with their values and cultural contexts, including Church and community—thereby enacting the call of EBM to integrate the best available research with patient preferences. Where children are concerned, the stakes are higher. They are, essentially, mandatedpatients—most do not have a voice to say no to treatments or devise their own, and depend on
  8. 8. 8adults to safeguard their wellbeing (Sparks & Duncan, 2008). Moreover, poor children oftenhave fewer adults watching over them and seem prone to dangerous drugs used as interventionsof control rather than therapy, and therefore require more care to ensure equitable treatment. Theevidence demands that the trend of rising prescriptions and lower psychosocial intervention bestopped and a higher standard of care implemented: 1) psychosocial intervention should beconsidered first--families and youth should have a voice in decisions about their care, especiallythe disenfranchised; 2) no off label prescribing; 3) no polypharmacy; 4) immediate separation ofthe pharmaceutical company influence from science and practice; and 5) monitoring treatmentresponse with patient rated measures. The belief in the power of chemistry over Church, community, social and psychologicalprocess—fueled by unprecedented promotion from the drug industry that targets all players inhealth care—forms the basis of pharmacology’s growing centrality in treatment, research,training, and practice. It promotes prescriptive treatments of questionable sustainability, fraughtwith potentially dangerous effects, often aimed at those most unable to refuse. This presentationcalled for a higher standard of care for our most vulnerable and precious commodity, ourchildren, that invites unity among all concerned health and pastoral professionals. It is time to nolonger accept prescriptive practices that do not follow the evidence and increasingly put clients atperilous risk for serious health consequences, dependence, and disability. The Catholic Church, in addition to spiritual leadership, has a rich history of benefitinghumanity, comforting and empowering the frail and disenfranchised, protecting the sanctity ofhuman life, and strengthening families. The Church and her vessels hold great internationalinfluence and perhaps may be the only power on earth that can counter the forces of corporategreed that has no moral or ethical conscience. The Church, via FIAMC, Catholic MedicalAssociations and Catholic hospitals, Catholic schools, Catholic Church communities, theCatholic media, in conjunction with bishops, priests, and sisters in religious communities, canassist individuals and families in need of guidance/education in alternatives to medication as wellas the appropriate risk/benefit discussions regarding the use of medication. For there to be social justice and equitable care for youth, health professionals, pastoralworkers, and families need access to accurate data--to the truth untainted by corporate influence.The risks presented here as well as the dangers of psychotropics emerging with other vulnerablepopulations (e.g., birth defects and spontaneous abortions in pregnant women on antidepressants;
  9. 9. 9increased heart attacks and strokes in the elderly with dementia on antipsychotics), offers a callto action to all of you attending this conference. Although a clinical trial will never address it, theuse of psychiatric drugs in paediatrics begs yet another question: How much do these drugsinterfere with the voice of the soul and ones ability to commune with the Divine?
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  13. 13. 13Smith, R. (2003). Medical journals and pharmaceutical companies: Uneasy bedfellows. British Medical Journal, 326, 1202-1205.Snyder, R., Turgay, A., Aman, M., Binder, C., Fisman, S., Carroll, A., et al. (2002). Effects of risperidone on conduct and disruptive behavior disorders in children with subaverage IQs. Journal of the American Academy of Child & Adolescent Psychiatry, 41(9), 1026-1036.Sparks, J., A. & Duncan, B. L. (2008). Do no harm: A critical risk/benefit analysis of child psychotropic medications. Journal of Family Psychotherapy,19 (1), 1-19.Sparks, J., Duncan, B., Cohen, D., & Antonuccio, D. (2010). Psychiatric drugs and common factors: An evaluation of risks and benefits for clinical practice. In B. Duncan, S. Miller, B. Wampold, & M. Hubble (Eds.), The heart and soul of change: Delivering what works in therapy. Washington D.C.: APA Books.Swanson, J. M., Elliott, G. R., Greenhill, L. L., Wigal, T., Arnold, L. E., et al. (2007). Effects of stimulant medication on growth rates across 3 years in the MTA follow-up. Journal of the American Academy of Child and Adolescent Psychiatry, 46(8), 1015-1027.Treatment for Adolescents with Depression Study (TADS) Team (2004). Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression. JAMA, 292(7), 807-820.The TADS Team (2007). The Treatment for Adolescents with Depression Study (TADS): Long-term effectiveness and safety outcomes. Archives of General Psychiatry, 64(10), 1132-1144.Turgay, L., Binder, C., Snyder, R., & Fisman, S. (2002). Long-term safety and efficacy of risperidone for the treatment of disruptive behavior disorders in children with subaverage IQs. Pediatrics, 110. Accessed June 9, 2007 from S. Food and Drug Administration (2003, January 3). FDA approves Prozac for pediatric use to treat depression and OCD. Retrieved January 25, 2003 from, J, Safer, D., Sai, D., Gardner, J., Thomas, D., Coombes, P., et al. (2008). Psychotropic medication patterns among youth in foster care. Pediatrics, 121, 157-163.