NEW RESEARCH PROVES THERE IS 'REASONABLE DOUBT ' ABOUT MEDICATING CHILDREN WITH PSYCHO-STIMULANTS? - SUDDEN DEATHS INCREASE IN CHILDREN TAKING STIMULANTS STUDY - LEADS TO F.D.A. (FEDERAL DRUG AGENCY) WARNING

APA PRODUCES THE AMERICAN JOURNAL OF PSYCHIATRY AND THE CONTROVERSIAL DSM4 - 5.

Sudden Death and Use of Stimulant Medications in Youths
Madelyn S. Gould, Ph.D., M.P.H., B. Timothy Walsh, M.D., Jimmie Lou Munfakh, B.A., Marjorie Kleinman, M.S., Naihua Duan, Ph.D., Mark Olfson, M.D., M.P.H., Laurence Greenhill, M.D., and Thomas Cooper, M.A. - 
THE AMERICAN JOURNAL OF PSYCHIATRY - JUNE 2009.





  

  Abstract

OBJECTIVE:
The authors sought to determine whether a significant association exists between the use of stimulants and the rare event of sudden unexplained death in children and adolescents.  
METHOD:
A matched case-control design was performed. Mortality data from 1985–1996 state vital statistics were used to identify 564 cases of sudden death occurring at ages 7 through 19 years across the United States along with a matched group of 564 young people who died as passengers in motor vehicle traffic accidents. The primary exposure measure was the presence of amphetamine, dextroamphetamine, methamphetamine, or methylphenidate according to informant reports or as noted in medical examiner records, toxicology results, or death certificates. 

RESULTS: 
In 10 (1.8%) of the sudden unexplained deaths it was determined that the youths were taking stimulants, specifically methylphenidate; in contrast, use of stimulants was found in only two subjects in the motor vehicle accident comparison group (0.4%), with only one involving methylphenidate use. A significant association of stimulant use with sudden unexplained death emerged from the primary analysis, which was based on exact conditional logistic regression (odds ratio=7.4, 95% CI=1.4 to 74.9). A comprehensive series of sensitivity analyses yielded qualitatively similar findings.

CONCLUSIONS: 
This case-control study provides support for an association between the use of stimulants and sudden unexplained death among children and adolescents. Although sudden unexplained death is a rare event, this finding should be considered in the context of other data about the risk and benefit of stimulants in medical treatment.

IF THERE IS A REASONABLE DOUBT ABOUT THE EFFICACY AND SAFETY OF PRESCRIBED STIMULANTS FOR CHILDREN, AS A SOCIETY WE SHOULD DECIDE NOT TO USE THEM.


  

  Introduction

Reports of sudden death among children and adolescents receiving stimulant medications for treatment of attention deficit hyperactivity disorder (ADHD) have raised concerns about the safety of these agents. There have been reports of pediatric stroke after long-term use of methylphenidate within therapeutic ranges (1). Acute myocardial infarction has been reported in one adolescent taking methylphenidate for an unknown period of time (2) and in another adolescent 1 week after restarting a daily 20-mg prescription of mixed amphetamine salts (3). Cardiac arrest occurred in another adolescent who was taking methylphenidate for ADHD and who had previously had a normal baseline echocardiogram (4). The Food and Drug Administration (FDA), using the Adverse Event Reporting System, reported 11 sudden deaths in pediatric patients taking methylphenidate from January 1992 to February 2005 (5). While the FDA’s reporting rate of sudden death in stimulant-treated children was the same as the base rate in the general population, spontaneous reports of sudden deaths may underestimate their true incidence, and limited available information on total number of prescriptions precludes reliable estimates of stimulant exposure (5). Less serious cardiovascular effects have also been reported in association with stimulant medications. An average increase in diastolic blood pressure of 4 mm Hg has been found among stimulant-treated youths in placebo-controlled trials (5, 6). A 10-year analysis of Florida Medicaid claims data revealed that stimulant use among youths diagnosed with ADHD was associated with increases of 20% and 21% in risk of emergency department visits and physician office visits for cardiac symptoms, respectively (7). No cardiac sudden deaths occurred during the 42,612 person-years of current stimulant use; however, as the authors noted, the rarity of sudden death and cardiac mortality in this age group would have necessitated a sample size 16 times larger, i.e., approximately 2,000,000 person-years, to detect a significant difference between the stimulant use and nonuse groups.

There continues to be controversy surrounding whether there exists an association between stimulant use for the treatment of ADHD and serious cardiovascular events, including sudden death, with accompanying debate over clinical recommendations for physicians and families (8, 9). The FDA’s Pediatric Advisory Committee in March of 2006 voted unanimously against a black box warning, which had been proposed by an earlier FDA advisory committee, but recommended a warning targeted to specific high-risk children, such as those with structural heart defects, cardiomyopathy, or heart-rhythm disturbances (10). In 2008, the American Heart Association recommended considering routine ECGs prior to starting children with ADHD on stimulant and other psychotropic therapy regimens (11) but underscored the need for future studies to assess the risk of sudden death associated with stimulant medication use in children and adolescents. The American Academy of Pediatrics (12) has also highlighted the "absence of scientific data to establish an increased risk of sudden death in individuals receiving stimulant medications."

The present article provides empirical data on the risk of sudden death and stimulant drug use in children and adolescents. In light of the rarity of sudden death in this age group (estimated at 0.8 to 8.5 cases per 100,000 patient-years) (13, 14), a matched case-control design was employed. The analysis seeks to estimate the strength of association between use of stimulant medications and sudden unexplained death.
  

  Method

This study was initiated in 1996, with support from the National Institute of Mental Health (NIMH), to examine the association between sudden death in children and adolescents and the use of tricyclic antidepressants or concomitant methylphenidate and clonidine therapy (15, 16). During the course of the study, there was a marked decrease in the use of tricyclic antidepressants in youths (17) and an associated significant increase in the use of selective serotonin reuptake inhibitors (SSRIs), which led to an attenuation of the clinical relevance of our examination of the association of tricyclic antidepressants and sudden death. Thus, these analyses were not pursued further. In light of concerns over the safety of stimulant medications, the FDA in 2006 requested an expansion of the inquiry of stimulants to include amphetamine, dextroamphetamine, and methamphetamine. The current report focuses on stimulant use among children and adolescents.

Definition of Sudden Unexplained Death
A case of sudden unexplained death was defined as any cause of death listed as ICD-9 codes E798 (sudden death, cause unknown), E799.9 (other unknown and unspecified causes), or E427 (cardiac dysrhythmia). These codes reflected causes of death in case reports of sudden death in children using tricyclic medications (15), consistent with the original goal of the study. We targeted cases 7 through 19 years of age, identified from mortality data from 1985 –1996 state vital statistics across the United States.

Exclusion criteria were 1) deaths with known causes—such as accidental deaths, suicides, overdoses, homicides, and natural causes (e.g., asthma)—initially misclassified on death certificate as unknown and subsequently amended; 2) deaths in which there were medical intervention complications or among individuals hospitalized for more than 48 hours at the time of death; or 3) coexisting physical disorders known or suspected to be associated with sudden death but not listed as the cause of death on the death certificate or autopsy report, such as Marfan’s syndrome (14), Wolff-Parkinson-White syndrome (18), severe cerebral palsy (19), profound developmental delays (20), seizure disorders (21), sickle cell anemia (22), morbid obesity (23), asthma (24), anorexia nervosa (25), prolonged QT interval in the deceased or in any first-degree relative, history of sudden death among first-degree relatives, conduction disorders in the deceased, and evidence of cardiac disease or abnormal anatomical finding on autopsy, such as cardiomegaly, cardiac hypertrophy, and cardiomyopathy (14).

Comparison Group
Individuals who died as passengers in motor vehicle traffic accidents with another motor vehicle (ICD-9 code E812.1) were also examined. A comparison group of deceased youngsters was necessary to avoid differential recall biases. Parents of both sudden unexplained death and motor vehicle accident victims had experienced a sudden, traumatic loss of their children. Unlike other victims of injuries (28), motor vehicle passenger victims were selected because they have been found not to be at greater risk for hyperactivity and other deficits in vigilance, attention, and impulse control. Thus, we avoided inappropriately increasing the likelihood of stimulant use among the comparison group. In this way, subjects were likely to be representative of the general population of youths 7 through 19 years of age. The same exclusion criteria noted for sudden unexplained death subjects were applied to the motor vehicle accident victims.

Comparison subjects were individually matched to sudden unexplained death cases by year of death (within 3 years), age (within 3 years), gender, and data source available. Each matched pair was unique; an individual motor vehicle accident victim was matched to one and only one case of sudden unexplained death. Limitations in the pool of comparison subjects precluded matching on race and census geographic region of death, factors that may affect rate of stimulant medication use (7, 26).

Definition of Exposure
The primary exposure variable was evidence of stimulant use immediately prior to death, indicated by presence of amphetamine, dextroamphetamine, methamphetamine, methylphenidate, or their derivatives, as noted by informants or in medical examiner records, toxicology findings, or death certificates. Information was also obtained about use of clonidine, tricyclic antidepressants, and SSRI antidepressants.

Sources of Data
Mortality data and death certificates were obtained from state vital statistics offices across the United States (including New York City and the District of Columbia) for 1985 through 1996. Indiana, Kansas, Maryland, Wisconsin, and Wyoming were excluded because their state statutes did not allow direct interviewing of families of deceased individuals or had restrictive contact requirements.

For informant reports, the names of the deceased child and his or her parents and the address at time of death were identified from the death certificate, on public record, from the state vital statistics offices. Parents were approached by letter describing the purpose of the study and were asked to complete a survey. The survey included items assessing medical history, medications taken at time of death, a list of medical problems, and the use of over-the-counter and prescription medications. A history of sudden death among relatives was also assessed. To locate informants, various Internet search engine white pages, a credit bureau database (without access to credit information), ChoicePoint (CDB Infotek), and PrivateEye were used.

Medical examiner records and toxicology findings were used to identify medication use and assist in the identification of exclusion criteria. Medical examiner reports could include informant- or toxicology-based findings, as well as autopsy reports. The applied postmortem detection threshold for a blood or urine stimulant level to be deemed positive varied considerably across jurisdictions. Thus, our reports of a positive finding reflect a value above the stated threshold for each individual laboratory.

Procedures
Data collection, from March 1997 to January 2008, involved the following phases. Cases of sudden unexplained death were identified through state mortality data, and death certificates were obtained from state vital statistics offices. Death certificates were reviewed for eligibility by the research team. Parents were approached for surveys and consent for records, if required by state law. Autopsy and toxicology records obtained from medical examiners were reviewed and abstracted. The same procedures were applied to motor vehicle accident victims matched to sudden unexplained death cases with surveys or toxicology results.

A two-stage determination of eligibility for all subjects was conducted by the two principal investigators (M.S.G. and B.T.W.) and research staff, blind to medication status. The first stage involved the examination of death certificates, and the second involved review of informant reports and medical examiner, autopsy, toxicology, and medical records.

The Institutional Review Board of the New York State Psychiatric Institute/Columbia University Department of Psychiatry approved study procedures, and a Certificate of Confidentiality was issued by NIMH.

Analytic Strategy
The basic unit of analysis is the matched dyad, rather than the individual subject. We estimated the association between sudden unexplained death and stimulant exposure using a logistic regression model that predicted sudden unexplained death from stimulant exposure. Race and region of death were included as covariates in all logistic regression models. In light of matching on sources of information (e.g., medical examiner records, toxicology, and informant reports), only sources available for both members of the matched pair were used to define exposure status. In the primary analysis, using the total sample, exposure was defined as any stimulant indication. A series of sensitivity analyses varied the exposure definition, including the presence of any stimulant as noted by informants; any stimulant reported in medical examiner records or toxicology reports; methylphenidate reported by any source; methylphenidate noted by informants; and methylphenidate disclosed in medical examiner records or toxicology reports. Each sensitivity analysis used the subsample of dyads with observed data for the specific information source.

In light of the original study’s intent to examine the association of sudden death with tricyclic antidepressants and with concomitant methylphenidate and clonidine use, we conducted another series of analyses to assess whether these associations might be significant in our sample in order to determine whether the concomitant use of these medications needed to be taken into account in our current sensitivity analyses of stimulant exposure.

Pairing of subjects (27) was incorporated into the conditional logistic regression model through exact conditional logistic regression using the EXACT statement in the LOGISTIC procedure in SAS statistical software, release 8.1.


  

  Results

Eligible individuals (N=926) were identified from a pool of 3,211 youths with deaths listed as ICD-9 codes E798, E799.9, or E427 (Figure 1). Table 1 provides the reasons for ineligibility. The overall study inclusion rate was 60.9% (N=564 of 926). Study exclusion was due largely to our inability to locate informants listed on the death certificates and obtain medical examiner or toxicology records. There were no significant differences in gender or race between the sudden unexplained death cases included and excluded from the study. However, there were significant differences in age, region of death, and year of death
  


aA two-stage determination of eligibility was conducted blind to medication status. The first stage involved the examination of death certificates; the second stage involved review of informant reports and medical examiner, autopsy, toxicology, and medical records.
  



The group of 564 comparison subjects was obtained from a potential pool of 1,014 motor vehicle passenger fatalities, identified from jurisdictions that conducted informative toxicology screens. Thus, 55.6% of the total pool of motor vehicle passenger fatalities were matched to a sudden unexplained death case. Table 2 displays the demographic characteristics of the sudden unexplained death cases included in the study and the motor vehicle accident comparison group; race and region of death significantly differed between the two groups. The distribution of the information sources available for the 564 matched pairs was as follows: informant reports only (29.6%); medical examiner records or toxicology reports only (55.5%); informant reports and medical examiner records but no toxicology report (5.3%); and all three sources (9.6%).

Matched Pair Analyses
Ten of the 564 sudden unexplained death cases (1.8%) were identified as having used stimulants at the time of their deaths (Table 3). In each of these cases, the stimulant detected was methylphenidate. Stimulants were identified in two of the 564 motor vehicle accident comparison subjects (0.4%). Detailed information on the dose or duration of stimulant use was not available. Rates of stimulant use among subjects fell within the range reported for the years of study (26, 28, 29). Results of the primary analysis and sensitivity analyses are presented in Table 4, and the rates of exposure in the groups for each of these analyses are presented in Figure 2. The odds ratio derived from the primary exact logistic regression was 7.4 (95% CI=1.4–74.9; p=0.02). Sensitivity analyses using alternative measures of stimulant exposure revealed qualitatively similar findings, indicating that qualitatively our finding is insensitive to the stimulant exposure algorithm. In particular, all odds ratios observed were clinically significant (30), with the smallest one being 4.2 for the scenario "any stimulant, limited to medical examiner/toxicology reports.

Preliminary analysis of the association of tricyclic antidepressants with sudden death indicated that they might be associated in our sample (six exposures among our sudden death cases and none among our motor vehicle accident comparison subjects). Thus, another series of sensitivity analyses, paralleling those described previously, was conducted deleting any individuals with concomitant tricyclic antidepressant and stimulant use (Table 4 and bottom half of Figure 2). The sensitivity analyses, excluding the stimulant-exposed sudden death case with concomitant tricyclic antidepressants, yielded essentially the same results, with the smallest odds ratio being 3.2, again for the scenario "any stimulant, limited to medical examiner/toxicology reports." The use of clonidine appeared not to be associated with sudden death, providing no justification to delete the case with concomitant clonidine and stimulants. In analyses with reduced numbers of total observations or exposures, some of the p values fell below statistical significance. However, the focus of sensitivity analysis is on the effect sizes (the odds ratios), which reflect the strength of the association, rather than the p values, which are a function of sample size (31).

Examination of Potential Biases
Threshold postmortem blood levels of detection of the targeted stimulant exposure varied by jurisdiction, raising the possibility that the thresholds for sudden unexplained death cases might be more sensitive than for the comparison group of motor vehicle accident victims. Mean threshold detection levels available for 83 cases of sudden unexplained death and 66 motor vehicle accident deaths indicated that their thresholds for methylphenidate were not significantly different (mean=127.7 ng/ml versus 108.8 ng/ml, respectively; t=1.2, df=147, p=0.23).

Since a matched comparison subject was only sought after the identification of a case with appropriate documents, the interval between date of death and informant survey was significantly longer for the comparison subjects (mean=12.8 years, SD=4.5) than the sudden unexplained death cases (mean=9.8 years, SD=5.2) (t=9.5, df=252, p<0.01), suggesting a possible recall bias. However, deleting all three motor vehicle accident victims whose death-to-survey interval was greater than two standard deviations above the mean of the sudden unexplained death cases did not change the results of the matched-pair analysis (odds ratio=7.3, 95% CI=1.4–74.0; p=0.02). Moreover, the death-to-survey interval was not significantly related to reports of stimulant exposure among sudden unexplained death cases (odds ratio=0.99, 95% CI=0.98–1.01; p=0.46). An informant survey was available for only one stimulant-exposed motor vehicle accident victim, precluding the inclusion of motor vehicle accident victims in a similar analysis. The distribution of informants did not significantly differ by group ({chi}2=8.1, df=6, p=0.23). A great majority of informants for sudden unexplained death cases (91.2%) and motor vehicle accident victims (93.2%) were parents/legal guardians, suggesting that differential recall bias is unlikely to be an important source of bias.
  

  Discussion

In recent years, concerns have arisen that stimulants may be associated with an increased risk of death. Results of the current study are consistent with these concerns. The odds of using stimulant medications were approximately six to seven times greater for the cases of sudden unexplained death than for the matched motor vehicle accident victims. Such an association is biologically plausible given the central and peripheral catecholaminergic effects of stimulants and significant increases in heart rate and blood pressure that accompany their use (32).

The present study has several strengths. First, it employed a matched case-control design, which yielded substantial power to detect rare outcomes. Second, multiple sources of information were used to increase the sensitivity of detecting stimulant use. Third, the availability of parent reports lessened the possibility that the findings reflect illicit stimulant use, since it is unlikely that parents would have known of or reported illicit stimulant use. The single youth who appeared likely to have used stimulants illicitly was a motor vehicle accident victim, whose "positive" exposure was detected by toxicology alone. Fourth, several potential confounding factors, such as asthma, that are associated with both ADHD (33) and sudden death (24), were excluded. Furthermore, because ADHD (34) and impaired attention (35) are common among youths with some congenital structural cardiac diseases, we excluded individuals with evidence of cardiomegaly, cardiac hypertrophy, and cardiomyopathy. Three individuals receiving stimulants were excluded from our group of sudden unexplained death cases because of notations of cardiac hypertrophy in their autopsies, even though the cardiac abnormalities were not cited as the cause of death. Moreover, we deleted a sudden death case with concomitant use of stimulants and tricyclic antidepressants, another possible confounding factor, in a second series of sensitivity analyses, and this had little effect on the results. Fifth, the study’s dates of inquiry (1985–1996) predated the use of Adderall, first approved by the FDA in 1996, which has been the stimulant medication most strongly implicated in sudden death (36).

The study also has important limitations. First, while case-control studies are a powerful method of detecting association, they cannot establish causality. It is conceivable that, despite our rigorous efforts to exclude or adjust for potential confounding factors, some unmeasured factors other than stimulant use were responsible for the observed association. For example, although gross structural cardiac disease was presumably excluded by autopsy, autopsy data were not available for two sudden unexplained death cases with stimulant exposure, and forensic pathology varies substantially in its ability to identify physiological as opposed to anatomic cardiovascular disease. Physiological abnormalities that confer risk (e.g., cardiac depolarization and repolarization abnormalities such as Brugada syndrome and long QT syndrome) could not be reliably excluded from the analysis. We attempted to exclude subjects with known prolonged QT interval, other conduction disorders, or a family history of long QT or sudden cardiac death, but clinically significant cardiac abnormalities may have passed undetected. However, a sensitivity analysis revealed that even if 40% of sudden unexplained death cases were excluded due to undetected cardiac disease, the primary analysis would still yield a significant association.

Second, we were unable to systematically obtain information on the psychiatric status of the decedents, including their clinical diagnoses. While this information was occasionally noted in a medical record or by an informant, it was not available for all subjects. Therefore, we are unable to estimate accurately the rates of ADHD in our sample, nor can we determine whether untreated ADHD was associated with sudden unexplained death. Although we excluded the known presence of structural cardiac diseases (24), as well as asthma (24, 33), there may be other unidentified mechanisms that were not controlled.

Third, we attempted to avoid differential recall biases, an important potential limitation of retrospective case-control studies, by employing a comparison group of deceased youths whose parents/legal guardians had also experienced a sudden, traumatic loss of their children. However, we cannot exclude the possibility that relative to a motor vehicle passenger fatality, an "unexplained" death may have prompted medical personnel to ask more questions about medications at the time of death. Yet the primary analysis remains significant (odds ratio=7.3, 95% CI=1.4–74.8, p=0.015) following exclusion of the one sudden unexplained death case whose methylphenidate exposure was detected solely from the medical examiner’s report. Although conceivable, we consider it unlikely that parents of sudden unexplained death cases remembered stimulant medications more vividly than parents of children who died in accidents. It is reassuring that medical records available for two sudden unexplained death cases whose "positive" exposures were based solely on the parental survey corroborated these informant reports. Because we were unable to obtain medical records on a majority of our subjects, we did not use them to identify "positive" exposures.

Fourth, toxicological assays were not conducted consistently across jurisdictions and may not have been sufficiently sensitive to detect therapeutic levels of methylphenidate, yielding an unreliable measure of exposure. The average detection threshold in toxicological assays (approximately 100 ng/ml) appeared to be higher than blood levels achieved during routine therapeutic use of immediate-release methylphenidate preparations (24 ng/ml) (37), or the even lower peak plasma levels of 8–10 ng/ml achieved by the more recently marketed single daily dose, long-duration methylphenidate preparations, such as OROS methylphenidate (38). The short half-life of methylphenidate (37, 39) and the interval between the last ingestion of medication and the acquisition of the blood samples is another potential source of insensitivity of the toxicology screens. Because sustained-release stimulants had not yet been widely marketed during the years of study (1985–1996), a therapeutic dose may not have remained in the blood for sufficient time to be detected by postmortem toxicology screens. This may explain why stimulants were not detected in the toxicology reports of five sudden unexplained death cases whose stimulant use was reported by the informant or noted in the medical examiner’s record (as reported by an informant at the time of death). Thus, while we are confident that the toxicology screens accurately ruled out overdoses, they may have been insensitive in some cases to therapeutic levels of methylphenidate. Nevertheless, since only sources of information available for both sudden unexplained death cases and matched motor vehicle fatality victims were used in the analyses, limitations in a particular source of exposure, whether toxicology records or informant reports, were comparable across groups. Moreover, sensitivity analyses suggest that qualitatively our results were not sensitive to method of stimulant measurement.

Fifth, we were able to include in our analyses only 61% of the eligible cases of sudden unexplained death. Although there were no significant differences in gender or race between included and excluded subjects, these groups did significantly differ in age, region, and year of death. Sudden unexplained death cases included in the study were significantly older, less likely to have died in the South, more likely to have died in the West, and more likely to have died in the later years of the study. Nationally representative studies indicate that stimulant use rates vary by age, region, and year (26, 28). Differences in age would likely have yielded lower rates of stimulant use among those included because age is inversely related to stimulant use (26, 28). Similarly, since the South has the highest rate of stimulant use and the West has the second lowest rate (26), rates of stimulant use among sudden unexplained death cases included in the study would likely have been lower than in those excluded. Conversely, the steep increase in the utilization of stimulants over time (26, 28, 29) would bias toward more stimulant use among the included than the excluded subjects. Although included subjects are not representative of all sudden unexplained death cases, pairs were either matched (age, gender, and date of death) or adjusted (race and region of death) for these sociodemographic and vital characteristics. Nevertheless, there may be unknown selection biases related to our inability to obtain information from all potential cases.

Last, because the project was originally funded to examine the association of sudden death and the use of tricyclic antidepressant medication, we did not include pediatric stroke and acute myocardial infarction, other causes of death linked to methylphenidate in case reports (1–3, 40). This may have yielded an underestimation of the association between sudden death and stimulant use.

This study reports a significant association or "signal" between sudden unexplained death and the use of stimulant medication, specifically methylphenidate. While the data have limitations that preclude a definitive conclusion, our findings draw attention to the potential risks of stimulant medications for children and adolescents, which warrant clinical attention and further study.


  

  Footnotes

Presented in part at the 55th annual meeting of the American Academy of Child and Adolescent Psychiatry, Chicago, Oct. 28–Nov. 2, 2008. Received April 4, 2009; revisions received April 13, April 27, and May 11, 2009; accepted May 12, 2009 (doi: 10.1176/appi.ajp.2009.09040472). From the Division of Child and Adolescent Psychiatry, Division of Clinical Therapeutics, Division of Biostatistics and Data Coordination, and Division of Clinical and Genetic Epidemiology, New York State Psychiatric Institute, New York; the Department of Psychiatry and Division of Child and Adolescent Psychiatry, Columbia University College of Physicians & Surgeons, New York; the Department of Epidemiology and Department of Biostatistics, Columbia University School of Public Health, New York; and the Analytical Psychopharmacology Laboratory, Nathan Kline Institute, Orangeburg, N.Y. Address correspondence and reprint requests to Dr. Gould, Division of Child and Adolescent Psychiatry, New York State Psychiatric Institute, 1051 Riverside Dr., New York, NY 10032; gouldm@childpsych.columbia.edu (e-mail).

Dr. Walsh has received research support from AstraZeneca. Dr. Duan has received research support from Pfizer. Dr. Olfson has received research funding from Eli Lilly and AstraZeneca and has worked as a consultant for AstraZeneca and Pfizer and as a speaker for Janssen. Dr. Greenhill has received research support from Johnson & Johnson, Otsuka, and Forest. The remaining authors report no competing interests.

Supported in part by a contract from the Food and Drug Administration and a grant from NIMH (R01-MH56250).

The authors thank Judi Forman for her role in the initial implementation of the project and Elizabeth Altschuler and Francesca Osuna for their assistance in the preparation of the manuscript.  

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    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. Arch Pediatr Adolesc Med 2003; 157:17–25[Abstract/Free Full Text]
    Strom BL (Eds.): Pharmacoepidemiology, 3rd Edition. Chichester, UK, John Wiley & Sons, 2000
    Matthews JN, Altman DG: Interaction 2: compare effect sizes not p values (statistics notes). BMJ 1996; 313:808[Free Full Text]
    Elia J: Cardiovascular monitoring of children with ADHD, in Proceedings of the 55th Annual Meeting of the American Academy of Child and Adolescent Psychiatry. Washington, DC, AACAP, 2008
    Leibson CL, Katusic SK, Barbaresi WJ, Ransom J, O’Brien PC: Use and costs of medical care for children and adolescents with and without attention-deficit/hyperactivity disorder. JAMA 2001; 285:60–66[Abstract/Free Full Text]
    Gothelf D, Gruber R, Presburger G, Dotan I, Brand-Gothelf A, Burg M, Inbar D, Steinberg T, Frisch A, Apter A, Weizman A: Methylphenidate treatment for attention-deficit/hyperactivity disorder in children and adolescents with velocardiofacial syndrome: an open-label study. J Clin Psychiatry 2003; 64:1163–1169[Medline]
    Kirshbom PM, Flynn TB, Clancy RR, Ittenbach RF, Hartman DM, Paridon SM, Wernovsky G, Spray TL, Gaynor JW: Late neurodevelopmental outcome after repair of total anomalous pulmonary venous connection. J Thoracic Cardiovascular Surgery 2005; 129:1091–1097[Abstract/Free Full Text]
    Food and Drug Administration: Adderall and Adderall XR (amphetamine). www.fda.gov/cder/drug/InfoSheets/HCP/AdderallHCPSheet.pdf (accessed Jan 2008)
    Birmaher B, Greenhill LL, Cooper TB, Fried J, Maminski B: Sustained release methylphenidate: pharmacokinetic studies in ADHD males. J Am Acad Child Adolesc Psychiatry 1989; 28:768–772[Medline]
    Modi NB, Wang B, Noveck RJ, Gupta SK: Dose-proportional and stereospecific pharmacokinetics of methylphenidate delivered using an osmotic, controlled-release oral delivery system. J Clin Pharmacol 2000; 40:1141–1149[Abstract]
    Wolraich ML, Doffing MA: Pharmacokinetic considerations in the treatment of attention-deficit hyperactivity disorder with methylphenidate. CNS Drugs 2004; 18:243–250[CrossRef][Medline]
    Schteinschnaider A, Plaghos LL, Garbugino S, Riveros D, Lazarowski A, Intruvini S, Massaro M: Cerebral arteritis following methylphenidate use. J Child Neurol 2000; 15:265–267[Abstract/Free Full Text]

SENATOR CHARLES GRASSLEY ADVOCATES - "WHILE YOU LIVE TELL THE TRUTH AND SHAME THE DEVIL"(WILLIAM SHAKESPEARE)-COURTESY OF THE NEW YORK BOOK REVIEW 2009- BY MARCIA ANGELL

 

"Drug Companies & Doctors: A Story of Corruption" 

Side Effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial
by Alison Bass
 
Algonquin Books of Chapel Hill, 260 pp., $24.95

Our Daily Meds: How the Pharmaceutical Companies Transformed Themselves into Slick Marketing Machines and 

Hooked the Nation on Prescription Drugs
by Melody Petersen
Sarah Crichton/Farrar, Straus and Giroux, 432 pp., $26.00

Shyness: How Normal Behavior Became a Sickness
by Christopher Lane
Yale University Press, 263 pp., $27.50; $18.00 (paper)

TO WATCH CHANNEL 4 'SPECIAL REPORT' CLICK ON LINK BELOW: 
http://www.channel4.com/news/adhd-drugs-prescribed-to-under-6s-against-guidelines

SENATOR CARLES (CHUCK) GRASSLEY LEADS THE EXPOSURE OF DRUG COMPANIES UNDUE INFLUENCE ON PSYCHIATRY.

Recently Senator Charles Grassley, ranking Republican on the Senate Finance Committee, has been looking into financial ties between the pharmaceutical industry and the academic physicians who largely determine the market value of prescription drugs. He hasn't had to look very hard.

Take the case of Dr. Joseph L. Biederman, professor of psychiatry at Harvard Medical School and chief of pediatric psychopharmacology at Harvard's Massachusetts General Hospital. Thanks largely to him, children as young as two years old are now being diagnosed with bipolar disorder and treated with a cocktail of powerful drugs, many of which were not approved by the Food and Drug Administration (FDA) for that purpose and none of which were approved for children below ten years of age.
Legally, physicians may use drugs that have already been approved for a particular purpose for any other purpose they choose, but such use should be based on good published scientific evidence. That seems not to be the case here. Biederman's own studies of the drugs he advocates to treat childhood bipolar disorder were, as The New York Times summarized the opinions of its expert sources, "so small and loosely designed that they were largely inconclusive."[1]
In June, Senator Grassley revealed that drug companies, including those that make drugs he advocates for childhood bipolar disorder, had paid Biederman $1.6 million in consulting and speaking fees between 2000 and 2007. Two of his colleagues received similar amounts. After the revelation, the president of the Massachusetts General Hospital and the chairman of its physician organization sent a letter to the hospital's physicians expressing not shock over the enormity of the conflicts of interest, but sympathy for the beneficiaries: "We know this is an incredibly painful time for these doctors and their families, and our hearts go out to them."
Or consider Dr. Alan F. Schatzberg, chair of Stanford's psychiatry department and president-elect of the American Psychiatric Association. Senator Grassley found that Schatzberg controlled more than $6 million worth of stock in Corcept Therapeutics, a company he cofounded that is testing mifepristone—the abortion drug otherwise known as RU-486—as a treatment for psychotic depression. At the same time, Schatzberg was the principal investigator on a National Institute of Mental Health grant that included research on mifepristone for this use and he was coauthor of three papers on the subject. In a statement released in late June, Stanford professed to see nothing amiss in this arrangement, although a month later, the university's counsel announced that it was temporarily replacing Schatzberg as principal investigator "to eliminate any misunderstanding."
Perhaps the most egregious case exposed so far by Senator Grassley is that of Dr. Charles B. Nemeroff, chair of Emory University's department of psychiatry and, along with Schatzberg, coeditor of the influential Textbook of Psychopharmacology.[2] Nemeroff was the principal investigator on a five-year $3.95 million National Institute of Mental Health grant—of which $1.35 million went to Emory for overhead—to study several drugs made by GlaxoSmithKline. To comply with university and government regulations, he was required to disclose to Emory income from GlaxoSmithKline, and Emory was required to report amounts over $10,000 per year to the National Institutes of Health, along with assurances that the conflict of interest would be managed or eliminated.
But according to Senator Grassley, who compared Emory's records with those from the company, Nemeroff failed to disclose approximately $500,000 he received from GlaxoSmithKline for giving dozens of talks promoting the company's drugs. In June 2004, a year into the grant, Emory conducted its own investigation of Nemeroff's activities, and found multiple violations of its policies. Nemeroff responded by assuring Emory in a memorandum, "In view of the NIMH/Emory/GSK grant, I shall limit my consulting to GSK to under $10,000/year and I have informed GSK of this policy." Yet that same year, he received $171,031 from the company, while he reported to Emory just $9,999—a dollar shy of the $10,000 threshold for reporting to the National Institutes of Health.
Emory benefited from Nemeroff's grants and other activities, and that raises the question of whether its lax oversight was influenced by its own conflicts of interest. As reported by Gardiner Harris in The New York Times,[3] Nemeroff himself had pointed out his value to Emory in a 2000 letter to the dean of the medical school, in which he justified his membership on a dozen corporate advisory boards by saying:

Surely you remember that Smith-Kline Beecham Pharmaceuticals donated an endowed chair to the department and there is some reasonable likelihood that Janssen Pharmaceuticals will do so as well. In addition, Wyeth-Ayerst Pharmaceuticals has funded a Research Career Development Award program in the department, and I have asked both AstraZeneca Pharmaceuticals and Bristol-Meyers [sic] Squibb to do the same. Part of the rationale for their funding our faculty in such a manner would be my service on these boards.

Because these psychiatrists were singled out by Senator Grassley, they received a great deal of attention in the press, but similar conflicts of interest pervade medicine. (The senator is now turning his attention to cardiologists.) Indeed, most doctors take money or gifts from drug companies in one way or another. Many are paid consultants, speakers at company-sponsored meetings, ghost-authors of papers written by drug companies or their agents,[4] and ostensible "researchers" whose contribution often consists merely of putting their patients on a drug and transmitting some token information to the company. Still more doctors are recipients of free meals and other out-and-out gifts. In addition, drug companies subsidize most meetings of professional organizations and most of the continuing medical education needed by doctors to maintain their state licenses.
No one knows the total amount provided by drug companies to physicians, but I estimate from the annual reports of the top nine US drug companies that it comes to tens of billions of dollars a year. By such means, the pharmaceutical industry has gained enormous control over how doctors evaluate and use its own products. Its extensive ties to physicians, particularly senior faculty at prestigious medical schools, affect the results of research, the way medicine is practiced, and even the definition of what constitutes a disease.
Consider the clinical trials by which drugs are tested in human subjects.[5] Before a new drug can enter the market, its manufacturer must sponsor clinical trials to show the Food and Drug Administration that the drug is safe and effective, usually as compared with a placebo or dummy pill. The results of all the trials (there may be many) are submitted to the FDA, and if one or two trials are positive—that is, they show effectiveness without serious risk—the drug is usually approved, even if all the other trials are negative. Drugs are approved only for a specified use—for example, to treat lung cancer—and it is illegal for companies to promote them for any other use.
But physicians may prescribe approved drugs "off label"—i.e., without regard to the specified use—and perhaps as many as half of all prescriptions are written for off-label purposes. After drugs are on the market, companies continue to sponsor clinical trials, sometimes to get FDA approval for additional uses, sometimes to demonstrate an advantage over competitors, and often just as an excuse to get physicians to prescribe such drugs for patients. (Such trials are aptly called "seeding" studies.)
Since drug companies don't have direct access to human subjects, they need to outsource their clinical trials to medical schools, where researchers use patients from teaching hospitals and clinics, or to private research companies (CROs), which organize office-based physicians to enroll their patients. Although CROs are usually faster, sponsors often prefer using medical schools, in part because the research is taken more seriously, but mainly because it gives them access to highly influential faculty physicians—referred to by the industry as "thought-leaders" or "key opinion leaders" (KOLs). These are the people who write textbooks and medical journal papers, issue practice guidelines (treatment recommendations), sit on FDA and other governmental advisory panels, head professional societies, and speak at the innumerable meetings and dinners that take place every year to teach clinicians about prescription drugs. Having KOLs like Dr. Biederman on the payroll is worth every penny spent.
A few decades ago, medical schools did not have extensive financial dealings with industry, and faculty investigators who carried out industry-sponsored research generally did not have other ties to their sponsors. But schools now have their own manifold deals with industry and are hardly in a moral position to object to their faculty behaving in the same way. A recent survey found that about two thirds of academic medical centers hold equity interest in companies that sponsor research within the same institution.[6] A study of medical school department chairs found that two thirds received departmental income from drug companies and three fifths received personal income.[7] In the 1980s medical schools began to issue guidelines governing faculty conflicts of interest but they are highly variable, generally quite permissive, and loosely enforced.
Because drug companies insist as a condition of providing funding that they be intimately involved in all aspects of the research they sponsor, they can easily introduce bias in order to make their drugs look better and safer than they are. Before the 1980s, they generally gave faculty investigators total responsibility for the conduct of the work, but now company employees or their agents often design the studies, perform the analysis, write the papers, and decide whether and in what form to publish the results. Sometimes the medical faculty who serve as investigators are little more than hired hands, supplying patients and collecting data according to instructions from the company.
In view of this control and the conflicts of interest that permeate the enterprise, it is not surprising that industry-sponsored trials published in medical journals consistently favor sponsors' drugs—largely because negative results are not published, positive results are repeatedly published in slightly different forms, and a positive spin is put on even negative results. A review of seventy-four clinical trials of antidepressants, for example, found that thirty-seven of thirty-eight positive studies were published.[8] But of the thirty-six negative studies, thirty-three were either not published or published in a form that conveyed a positive outcome. It is not unusual for a published paper to shift the focus from the drug's intended effect to a secondary effect that seems more favorable.
The suppression of unfavorable research is the subject of Alison Bass's engrossing book, Side Effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial. This is the story of how the British drug giant GlaxoSmithKline buried evidence that its top-selling antidepressant, Paxil, was ineffective and possibly harmful to children and adolescents. Bass, formerly a reporter for the Boston Globe, describes the involvement of three people—a skeptical academic psychiatrist, a morally outraged assistant administrator in Brown University's department of psychiatry (whose chairman received in 1998 over $500,000 in consulting fees from drug companies, including GlaxoSmithKline), and an indefatigable New York assistant attorney general. They took on GlaxoSmithKline and part of the psychiatry establishment and eventually prevailed against the odds.
The book follows the individual struggles of these three people over many years, culminating with GlaxoSmithKline finally agreeing in 2004 to settle charges of consumer fraud for $2.5 million (a tiny fraction of the more than $2.7 billion in yearly Paxil sales about that time). It also promised to release summaries of all clinical trials completed after December 27, 2000. Of much greater significance was the attention called to the deliberate, systematic practice of suppressing unfavorable research results, which would never have been revealed without the legal discovery process. Previously undisclosed, one of GlaxoSmithKline's internal documents said, "It would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine [Paxil]."[9]
Many drugs that are assumed to be effective are probably little better than placebos, but there is no way to know because negative results are hidden. One clue was provided six years ago by four researchers who, using the Freedom of Information Act, obtained FDA reviews of every placebo-controlled clinical trial submitted for initial approval of the six most widely used antidepressant drugs approved between 1987 and 1999—Prozac, Paxil, Zoloft, Celexa, Serzone, and Effexor.[10] They found that on average, placebos were 80 percent as effective as the drugs. The difference between drug and placebo was so small that it was unlikely to be of any clinical significance. The results were much the same for all six drugs: all were equally ineffective. But because favorable results were published and unfavorable results buried (in this case, within the FDA), the public and the medical profession believed these drugs were potent antidepressants.
Clinical trials are also biased through designs for research that are chosen to yield favorable results for sponsors. For example, the sponsor's drug may be compared with another drug administered at a dose so low that the sponsor's drug looks more powerful. Or a drug that is likely to be used by older people will be tested in young people, so that side effects are less likely to emerge. A common form of bias stems from the standard practice of comparing a new drug with a placebo, when the relevant question is how it compares with an existing drug. In short, it is often possible to make clinical trials come out pretty much any way you want, which is why it's so important that investigators be truly disinterested in the outcome of their work.
Conflicts of interest affect more than research. They also directly shape the way medicine is practiced, through their influence on practice guidelines issued by professional and governmental bodies, and through their effects on FDA decisions. A few examples: in a survey of two hundred expert panels that issued practice guidelines, one third of the panel members acknowledged that they had some financial interest in the drugs they considered.[11] In 2004, after the National Cholesterol Education Program called for sharply lowering the desired levels of "bad" cholesterol, it was revealed that eight of nine members of the panel writing the recommendations had financial ties to the makers of cholesterol-lowering drugs.[12] Of the 170 contributors to the most recent edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM), ninety-five had financial ties to drug companies, including all of the contributors to the sections on mood disorders and schizophrenia.[13] Perhaps most important, many members of the standing committees of experts that advise the FDA on drug approvals also have financial ties to the pharmaceutical industry.[14]
In recent years, drug companies have perfected a new and highly effective method to expand their markets. Instead of promoting drugs to treat diseases, they have begun to promote diseases to fit their drugs. The strategy is to convince as many people as possible (along with their doctors, of course) that they have medical conditions that require long-term drug treatment. Sometimes called "disease-mongering," this is a focus of two new books: Melody Petersen's Our Daily Meds: How the Pharmaceutical Companies Transformed Themselves into Slick Marketing Machines and Hooked the Nation on Prescription Drugs and Christopher Lane's Shyness: How Normal Behavior Became a Sickness.
To promote new or exaggerated conditions, companies give them serious-sounding names along with abbreviations. Thus, heartburn is now "gastro-esophageal reflux disease" or GERD; impotence is "erectile dysfunction" or ED; premenstrual tension is "premenstrual dysphoric disorder" or PMMD; and shyness is "social anxiety disorder" (no abbreviation yet). Note that these are ill-defined chronic conditions that affect essentially normal people, so the market is huge and easily expanded. For example, a senior marketing executive advised sales representatives on how to expand the use of Neurontin: "Neurontin for pain, Neurontin for monotherapy, Neurontin for bipolar, Neurontin for everything."[15] It seems that the strategy of the drug marketers—and it has been remarkably successful—is to convince Americans that there are only two kinds of people: those with medical conditions that require drug treatment and those who don't know it yet. While the strategy originated in the industry, it could not be implemented without the complicity of the medical profession.
Melody Petersen, who was a reporter for The New York Times, has written a broad, convincing indictment of the pharmaceutical industry.[16] She lays out in detail the many ways, both legal and illegal, that drug companies can create "blockbusters" (drugs with yearly sales of over a billion dollars) and the essential role that KOLs play. Her main example is Neurontin, which was initially approved only for a very narrow use—to treat epilepsy when other drugs failed to control seizures. By paying academic experts to put their names on articles extolling Neurontin for other uses—bipolar disease, post-traumatic stress disorder, insomnia, restless legs syndrome, hot flashes, migraines, tension headaches, and more—and by funding conferences at which these uses were promoted, the manufacturer was able to parlay the drug into a blockbuster, with sales of $2.7 billion in 2003. The following year, in a case covered extensively by Petersen for the Times, Pfizer pleaded guilty to illegal marketing and agreed to pay $430 million to resolve the criminal and civil charges against it. A lot of money, but for Pfizer, it was just the cost of doing business, and well worth it because Neurontin continued to be used like an all-purpose tonic, generating billions of dollars in annual sales.
Christopher Lane's book has a narrower focus—the rapid increase in the number of psychiatric diagnoses in the American population and in the use of psychoactive drugs (drugs that affect mental states) to treat them. Since there are no objective tests for mental illness and the boundaries between normal and abnormal are often uncertain, psychiatry is a particularly fertile field for creating new diagnoses or broadening old ones.[17] Diagnostic criteria are pretty much the exclusive province of the current edition of the Diagnostic and Statistical Manual of Mental Disorders, which is the product of a panel of psychiatrists, most of whom, as I mentioned earlier, had financial ties to the pharmaceutical industry. Lane, a research professor of literature at Northwestern University, traces the evolution of the DSM from its modest beginnings in 1952 as a small, spiral-bound handbook (DSM-I) to its current 943-page incarnation (the revised version of DSM-IV) as the undisputed "bible" of psychiatry—the standard reference for courts, prisons, schools, insurance companies, emergency rooms, doctors' offices, and medical facilities of all kinds.
Given its importance, you might think that the DSM represents the authoritative distillation of a large body of scientific evidence. But Lane, using unpublished records from the archives of the American Psychiatric Association and interviews with the principals, shows that it is instead the product of a complex of academic politics, personal ambition, ideology, and, perhaps most important, the influence of the pharmaceutical industry. What the DSM lacks is evidence. Lane quotes one contributor to the DSM-III task force:

There was very little systematic research, and much of the research that existed was really a hodgepodge—scattered, inconsistent, and ambiguous. I think the majority of us recognized that the amount of good, solid science upon which we were making our decisions was pretty modest. Lane uses shyness as his case study of disease-mongering in psychiatry. Shyness as a psychiatric illness made its debut as "social phobia" in DSM-III in 1980, but was said to be rare. By 1994, when DSM-IV was published, it had become "social anxiety disorder," now said to be extremely common. According to Lane, GlaxoSmithKline, hoping to boost sales for its antidepressant, Paxil, decided to promote social anxiety disorder as "a severe medical condition." In 1999, the company received FDA approval to market the drug for social anxiety disorder. It launched an extensive media campaign to do it, including posters in bus shelters across the country showing forlorn individuals and the words "Imagine being allergic to people...," and sales soared. Barry Brand, Paxil's product director, was quoted as saying, "Every marketer's dream is to find an unidentified or unknown market and develop it. That's what we were able to do with social anxiety disorder."

Some of the biggest blockbusters are psychoactive drugs. The theory that psychiatric conditions stem from a biochemical imbalance is used as a justification for their widespread use, even though the theory has yet to be proved. Children are particularly vulnerable targets. What parents dare say "No" when a physician says their difficult child is sick and recommends drug treatment? We are now in the midst of an apparent epidemic of bipolar disease in children (which seems to be replacing attention-deficit hyperactivity disorder as the most publicized condition in childhood), with a forty-fold increase in the diagnosis between 1994 and 2003.[18] These children are often treated with multiple drugs off-label, many of which, whatever their other properties, are sedating, and nearly all of which have potentially serious side effects.
The problems I've discussed are not limited to psychiatry, although they reach their most florid form there. Similar conflicts of interest and biases exist in virtually every field of medicine, particularly those that rely heavily on drugs or devices. It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of The New England Journal of Medicine.
One result of the pervasive bias is that physicians learn to practice a very drug-intensive style of medicine. Even when changes in lifestyle would be more effective, doctors and their patients often believe that for every ailment and discontent there is a drug. Physicians are also led to believe that the newest, most expensive brand-name drugs are superior to older drugs or generics, even though there is seldom any evidence to that effect because sponsors do not usually compare their drugs with older drugs at equivalent doses. In addition, physicians, swayed by prestigious medical school faculty, learn to prescribe drugs for off-label uses without good evidence of effectiveness.
It is easy to fault drug companies for this situation, and they certainly deserve a great deal of blame. Most of the big drug companies have settled charges of fraud, off-label marketing, and other offenses. TAP Pharmaceuticals, for example, in 2001 pleaded guilty and agreed to pay $875 million to settle criminal and civil charges brought under the federal False Claims Act over its fraudulent marketing of Lupron, a drug used for treatment of prostate cancer. In addition to GlaxoSmithKline, Pfizer, and TAP, other companies that have settled charges of fraud include Merck, Eli Lilly, and Abbott. The costs, while enormous in some cases, are still dwarfed by the profits generated by these illegal activities, and are therefore not much of a deterrent. Still, apologists might argue that the pharmaceutical industry is merely trying to do its primary job—further the interests of its investors—and sometimes it goes a little too far.
Physicians, medical schools, and professional organizations have no such excuse, since their only fiduciary responsibility is to patients. The mission of medical schools and teaching hospitals—and what justifies their tax-exempt status—is to educate the next generation of physicians, carry out scientifically important research, and care for the sickest members of society. It is not to enter into lucrative commercial alliances with the pharmaceutical industry. As reprehensible as many industry practices are, I believe the behavior of much of the medical profession is even more culpable.[19] Drug companies are not charities; they expect something in return for the money they spend, and they evidently get it or they wouldn't keep paying.
So many reforms would be necessary to restore integrity to clinical research and medical practice that they cannot be summarized briefly. Many would involve congressional legislation and changes in the FDA, including its drug approval process. But there is clearly also a need for the medical profession to wean itself from industry money almost entirely. Although industry–academic collaboration can make important scientific contributions, it is usually in carrying out basic research, not clinical trials, and even here, it is arguable whether it necessitates the personal enrichment of investigators. Members of medical school faculties who conduct clinical trials should not accept any payments from drug companies except research support, and that support should have no strings attached, including control by drug companies over the design, interpretation, and publication of research results.
Medical schools and teaching hospitals should rigorously enforce that rule, and should not enter into deals with companies whose products members of their faculty are studying. Finally, there is seldom a legitimate reason for physicians to accept gifts from drug companies, even small ones, and they should pay for their own meetings and continuing education.
After much unfavorable publicity, medical schools and professional organizations are beginning to talk about controlling conflicts of interest, but so far the response has been tepid. They consistently refer to "potential" conflicts of interest, as though that were different from the real thing, and about disclosing and "managing" them, not about prohibiting them. In short, there seems to be a desire to eliminate the smell of corruption, while keeping the money. Breaking the dependence of the medical profession on the pharmaceutical industry will take more than appointing committees and other gestures. It will take a sharp break from an extremely lucrative pattern of behavior. But if the medical profession does not put an end to this corruption voluntarily, it will lose the confidence of the public, and the government (not just Senator Grassley) will step in and impose regulation. No one in medicine wants that.
Notes
[1]Gardiner Harris and Benedict Carey, "Researchers Fail to Reveal Full Drug Pay," The New York Times, June 8, 2008.
[2]Most of the information in these paragraphs, including Nemeroff's quote in the summer of 2004, is drawn from a long letter written by Senator Grassley to James W. Wagner, President of Emory University, on October 2, 2008.
[3]See Gardiner Harris, "Leading Psychiatrist Didn't Report Drug Makers' Pay," The New York Times, October 4, 2008.
[4]Senator Grassley is current investigating Wyeth for paying a medical writing firm to ghost-write articles favorable to its hormone-replacement drug Prempro.
[5]Some of this material is drawn from my article "Industry-Sponsored Clinical Research: A Broken System," The Journal of the American Medical Association, September 3, 2008.
[6]Justin E. Bekelman et al., "Scope and Impact of Financial Conflicts of Interest in Biomedical Research: A Systematic Review." 
 Recently Senator Charles Grassley, ranking Republican on the Senate Finance Committee, has been looking into financial ties between the pharmaceutical industry and the academic physicians who largely determine the market value of prescription drugs. He hasn’t had to look very hard.

Take the case of Dr. Joseph L. Biederman, professor of psychiatry at Harvard Medical School and chief of pediatric psychopharmacology at Harvard’s Massachusetts General Hospital. Thanks largely to him, children as young as two years old are now being diagnosed with bipolar disorder and treated with a cocktail of powerful drugs, many of which were not approved by the Food and Drug Administration (FDA) for that purpose and none of which were approved for children below ten years of age.

Legally, physicians may use drugs that have already been approved for a particular purpose for any other purpose they choose, but such use should be based on good published scientific evidence. That seems not to be the case here. Biederman’s own studies of the drugs he advocates to treat childhood bipolar disorder were, as The New York Times summarized the opinions of its expert sources, “so small and loosely designed that they were largely inconclusive.”1

In June, Senator Grassley revealed that drug companies, including those that make drugs he advocates for childhood bipolar disorder, had paid Biederman $1.6 million in consulting and speaking fees between 2000 and 2007. Two of his colleagues received similar amounts. After the revelation, the president of the Massachusetts General Hospital and the chairman of its physician organization sent a letter to the hospital’s physicians expressing not shock over the enormity of the conflicts of interest, but sympathy for the beneficiaries: “We know this is an incredibly painful time for these doctors and their families, and our hearts go out to them.”

Or consider Dr. Alan F. Schatzberg, chair of Stanford’s psychiatry department and president-elect of the American Psychiatric Association. Senator Grassley found that Schatzberg controlled more than $6 million worth of stock in Corcept Therapeutics, a company he cofounded that is testing mifepristone—the abortion drug otherwise known as RU-486—as a treatment for psychotic depression. At the same time, Schatzberg was the principal investigator on a National Institute of Mental Health grant that included research on mifepristone for this use and he was coauthor of three papers on the subject. In a statement released in late June, Stanford professed to see nothing amiss in this arrangement, although a month later, the university’s counsel announced that it was temporarily replacing Schatzberg as principal investigator “to eliminate any misunderstanding.”
Bloomsbury / Spring Titles

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Perhaps the most egregious case exposed so far by Senator Grassley is that of Dr. Charles B. Nemeroff, chair of Emory University’s department of psychiatry and, along with Schatzberg, coeditor of the influential Textbook of Psychopharmacology.2 Nemeroff was the principal investigator on a five-year $3.95 million National Institute of Mental Health grant—of which $1.35 million went to Emory for overhead—to study several drugs made by GlaxoSmithKline. To comply with university and government regulations, he was required to disclose to Emory income from GlaxoSmithKline, and Emory was required to report amounts over $10,000 per year to the National Institutes of Health, along with assurances that the conflict of interest would be managed or eliminated.

But according to Senator Grassley, who compared Emory’s records with those from the company, Nemeroff failed to disclose approximately $500,000 he received from GlaxoSmithKline for giving dozens of talks promoting the company’s drugs. In June 2004, a year into the grant, Emory conducted its own investigation of Nemeroff’s activities, and found multiple violations of its policies. Nemeroff responded by assuring Emory in a memorandum, “In view of the NIMH/Emory/GSK grant, I shall limit my consulting to GSK to under $10,000/year and I have informed GSK of this policy.” Yet that same year, he received $171,031 from the company, while he reported to Emory just $9,999—a dollar shy of the $10,000 threshold for reporting to the National Institutes of Health.

Emory benefited from Nemeroff’s grants and other activities, and that raises the question of whether its lax oversight was influenced by its own conflicts of interest. As reported by Gardiner Harris in TheNew York Times,3 Nemeroff himself had pointed out his value to Emory in a 2000 letter to the dean of the medical school, in which he justified his membership on a dozen corporate advisory boards by saying:

    Surely you remember that Smith-Kline Beecham Pharmaceuticals donated an endowed chair to the department and there is some reasonable likelihood that Janssen Pharmaceuticals will do so as well. In addition, Wyeth-Ayerst Pharmaceuticals has funded a Research Career Development Award program in the department, and I have asked both AstraZeneca Pharmaceuticals and Bristol-Meyers [sic] Squibb to do the same. Part of the rationale for their funding our faculty in such a manner would be my service on these boards.

Because these psychiatrists were singled out by Senator Grassley, they received a great deal of attention in the press, but similar conflicts of interest pervade medicine. (The senator is now turning his attention to cardiologists.) Indeed, most doctors take money or gifts from drug companies in one way or another. Many are paid consultants, speakers at company-sponsored meetings, ghost-authors of papers written by drug companies or their agents,4 and ostensible “researchers” whose contribution often consists merely of putting their patients on a drug and transmitting some token information to the company. Still more doctors are recipients of free meals and other out-and-out gifts. In addition, drug companies subsidize most meetings of professional organizations and most of the continuing medical education needed by doctors to maintain their state licenses.

No one knows the total amount provided by drug companies to physicians, but I estimate from the annual reports of the top nine US drug companies that it comes to tens of billions of dollars a year. By such means, the pharmaceutical industry has gained enormous control over how doctors evaluate and use its own products. Its extensive ties to physicians, particularly senior faculty at prestigious medical schools, affect the results of research, the way medicine is practiced, and even the definition of what constitutes a disease.

Consider the clinical trials by which drugs are tested in human subjects.5 Before a new drug can enter the market, its manufacturer must sponsor clinical trials to show the Food and Drug Administration that the drug is safe and effective, usually as compared with a placebo or dummy pill. The results of all the trials (there may be many) are submitted to the FDA, and if one or two trials are positive—that is, they show effectiveness without serious risk—the drug is usually approved, even if all the other trials are negative. Drugs are approved only for a specified use—for example, to treat lung cancer—and it is illegal for companies to promote them for any other use.

But physicians may prescribe approved drugs “off label”—i.e., without regard to the specified use—and perhaps as many as half of all prescriptions are written for off-label purposes. After drugs are on the market, companies continue to sponsor clinical trials, sometimes to get FDA approval for additional uses, sometimes to demonstrate an advantage over competitors, and often just as an excuse to get physicians to prescribe such drugs for patients. (Such trials are aptly called “seeding” studies.)

Since drug companies don’t have direct access to human subjects, they need to outsource their clinical trials to medical schools, where researchers use patients from teaching hospitals and clinics, or to private research companies (CROs), which organize office-based physicians to enroll their patients. Although CROs are usually faster, sponsors often prefer using medical schools, in part because the research is taken more seriously, but mainly because it gives them access to highly influential faculty physicians—referred to by the industry as “thought-leaders” or “key opinion leaders” (KOLs). These are the people who write textbooks and medical journal papers, issue practice guidelines (treatment recommendations), sit on FDA and other governmental advisory panels, head professional societies, and speak at the innumerable meetings and dinners that take place every year to teach clinicians about prescription drugs. Having KOLs like Dr. Biederman on the payroll is worth every penny spent.

A few decades ago, medical schools did not have extensive financial dealings with industry, and faculty investigators who carried out industry-sponsored research generally did not have other ties to their sponsors. But schools now have their own manifold deals with industry and are hardly in a moral position to object to their faculty behaving in the same way. A recent survey found that about two thirds of academic medical centers hold equity interest in companies that sponsor research within the same institution.6 A study of medical school department chairs found that two thirds received departmental income from drug companies and three fifths received personal income.7 In the 1980s medical schools began to issue guidelines governing faculty conflicts of interest but they are highly variable, generally quite permissive, and loosely enforced.

Because drug companies insist as a condition of providing funding that they be intimately involved in all aspects of the research they sponsor, they can easily introduce bias in order to make their drugs look better and safer than they are. Before the 1980s, they generally gave faculty investigators total responsibility for the conduct of the work, but now company employees or their agents often design the studies, perform the analysis, write the papers, and decide whether and in what form to publish the results. Sometimes the medical faculty who serve as investigators are little more than hired hands, supplying patients and collecting data according to instructions from the company.

In view of this control and the conflicts of interest that permeate the enterprise, it is not surprising that industry-sponsored trials published in medical journals consistently favor sponsors’ drugs—largely because negative results are not published, positive results are repeatedly published in slightly different forms, and a positive spin is put on even negative results. A review of seventy-four clinical trials of antidepressants, for example, found that thirty-seven of thirty-eight positive studies were published.8 But of the thirty-six negative studies, thirty-three were either not published or published in a form that conveyed a positive outcome. It is not unusual for a published paper to shift the focus from the drug’s intended effect to a secondary effect that seems more favorable.

The suppression of unfavorable research is the subject of Alison Bass’s engrossing book, Side Effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial. This is the story of how the British drug giant GlaxoSmithKline buried evidence that its top-selling antidepressant, Paxil, was ineffective and possibly harmful to children and adolescents. Bass, formerly a reporter for the Boston Globe, describes the involvement of three people—a skeptical academic psychiatrist, a morally outraged assistant administrator in Brown University’s department of psychiatry (whose chairman received in 1998 over $500,000 in consulting fees from drug companies, including GlaxoSmithKline), and an indefatigable New York assistant attorney general. They took on GlaxoSmithKline and part of the psychiatry establishment and eventually prevailed against the odds.

    1
    2
    3
    →

    1

    Gardiner Harris and Benedict Carey, "Researchers Fail to Reveal Full Drug Pay," The New York Times, June 8, 2008.↩
    2

    Most of the information in these paragraphs, including Nemeroff's quote in the summer of 2004, is drawn from a long letter written by Senator Grassley to James W. Wagner, President of Emory University, on October 2, 2008.↩
    3

    See Gardiner Harris, "Leading Psychiatrist Didn't Report Drug Makers' Pay," The New York Times, October 4, 2008.↩
    4

    Senator Grassley is current investigating Wyeth for paying a medical writing firm to ghost-write articles favorable to its hormone-replacement drug Prempro.↩
    5

    Some of this material is drawn from my article "Industry-Sponsored Clinical Research: A Broken System," TheJournal of the American Medical Association, September 3, 2008.↩
    6

    Justin E. Bekelman et al., "Scope and Impact of Financial Conflicts of Interest in Biomedical Research: A Systematic Review," The Journal of the American Medical Association, January 22, 2003.↩
    7

    Eric G. Campbell et al., "Institutional Academic–Industry Relationships," The Journal of the American Medical Association, October 17, 2007.↩
    8

    Erick H. Turner et al., "Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy," The New England Journal of Medicine, January 17, 2008.↩

DR ALLEN FRANCES - URGENTLY POINTS OUT - 'THE FUTURE IS CLOSING IN' - DSM5 IS DANGEROUSLY CLOSE - DR ALLEN FRANCES WARNS- COURTESY OF PSYCHOLOGY TODAY WEBSITE

DSM 5 Keeps Missing Its Deadlines
"The future is closing in."
Published on April 8, 2011 by Allen J. Frances, M.D. in 'DSM5 in Distress'

DR ALLEN FRANCES, LEAD EDITOR OF THE DSM4 TEAM IN 1995.

Aside from its reckless proposals for dangerous new diagnoses, the most characteristic thing about DSM-5 has been its remarkably poor planning and its consistently missed deadlines. By ambitiously over promising and then inefficiently under delivering, DSM-5 finds itself forever falling far behind its own scheduling targets, which then must constantly be pushed further and further into the future. But the future is now closing in on DSM-5. Its propensity for procrastination has already compromised the diagnostic coding system and suggests that the DSM 5 endgame will not be pretty.

Let's track the past first. When work on DSM-5 started in 2007, its date of publication was planned to be May, 2011. That's right folks- DSM 5 was originally meant to be on the bookshelves by next month. Soon it became clear that this original publication date was too optimistic and would have to be postponed until May 2012. Why the delay? The DSM 5 leadership had greatly underestimated the time it would take to vet workgroup members for financial conflicts of interest. This turned out to be just the first in a series of repeated planning and execution snafus, all resulting in constantly missed deadlines.
When it finally did get underway,, the work on DSM-5 quickly elicited widespread concerns about its closed and ineffective process. Early dire predictions about the weaknesses of DSM 5 planning and methods turned out to be accurate. There were multiple and unaccountable delays in the public posting of the proposed DSM-5 drafts and these turned out to be poorly thought out and of surprisingly poor overall quality. In August 2009, the APA responded to outside pressure by appointing a DSM-5 oversight committee. Apparently this group was able quickly to recognize the poor state and weak methods of the revision and in November 2009, the publication of DSM-5 had to be pushed back for yet another year- now to May 2013.

But all this extra time has been largely wasted. DSM 5 keeps managing to find ways of falling further behind its frequently postponed new target dates. It now seems doubtful that APA will meet its latest May 2013 deadline with anything approaching a quality product. DSM-5 will most likely either be late once again or it will be very sloppy - or perhaps both.

Extra time gained through extensions has been wasted in different ways. First, there is absolutely no excuse for not having the first drafts written on time and to a high level of quality. Instead the DSM 5 drafts were always submitted late and are still written so clumsily that (unless they are subjected to thorough and expert editing) they will cause great confusion to clinical and research practice.

The next fiasco was the impossibly complicated and poorly designed field trial which was introduced so late in the day that it could never receive a sorely needed externally review. The outcome is in an incredibly expensive and time consuming project that completely misses the point and is a total waste of time, effort, and money. . It should have been patently obvious (but wasn't to the DSM-5 leadership) that the field trials could never possibly be completed in the few months that were allotted to them. To make matters much worse, the typical DSM-5 administrative inefficiency resulted in an at least an eight month delay trailing its revised start date- which had already been postponed for almost a year from June 2009 to May 2010. Things have gotten so far behind and there is so much work left to do with so little coherence in how the work is being done that to have anything approaching a reasonable DSM 5 will probably require another delay pushing back the May 2013 publication date. The only alternative will be the acceptance of an incredibly disorganized DSM 5.

And it gets even worse. An article by the DSM 5 leadership in Psychiatric Research Reports (PRR) reveals between its lines that there has already been another serious casualty caused by all these unnecessary delays. It seems likely that the work on DSM-5 will have little impact on the official ICD-10-CM diagnostic coding system soon to be required for use by all clinicians. Diagnostic coding may seem an arcane and technical subject- and, in fact, in some ways, it is.

But in its own quiet way, coding is also crucially important. All medical and psychiatric encounters require a diagnosis and also a diagnostic code that is used for record keeping, compiling statistics, and determining reimbursement. The more precise the diagnostic code, the more information about the patient is communicated to the system, allowing for more sensitive research, administrative, and reimbursement decisions. For example, the ability to indicate the severity of a mood episode (included in the current coding system, ICD-9-CM) allows for the allocation of additional resources for more severe cases of depression.

It is important to understand that there is no such thing as a "DSM code." By international treaty, all health coding used for reporting all diseases and disorders in the United States is based on the International Classification of Disease (ICD) coding system developed by the World Health Organization in Geneva. The US adaptation of the ICD is known as ICD-CM (International Classification of Diseases-Clinical Modification) and is developed under the authority of the National Center of Health Care Statistics (NCHS), an agency of the US government.

The coding system currently in use in the US is ICD-9-CM, first made official in 1977. All of the DSM IV codes you have used all these years are really ICD-9-CM codes. We worked with the NCHS to adjust the ICD-9-CM system so that as many DSM-IV disorders and subtypes as possible would have unique ICD-9-CM codes. When we were preparing DSM-IV twenty years ago, we also did our best to increase compatibility with the WHO's new ICD-10 system which was being developed at the same time. We expected that, within a few years, the US version of ICD-10-CM would be implemented. Working closely with NCHS, the mental disorders section of ICD-10-CM was tailored to be virtually identical to DSM-IV so that every DSM-IV disorder and many of its most important specifiers would have its unique ICD-10-CM code.

To everyone's surprise, once prepared ICD-10-CM wound up sitting on the shelf for the next 15 years- because of a combination of bureaucratic foot-dragging and concern about the high cost of switching systems. Several years ago the US Government finally announced that ICD-10-CM would become the official coding system in the US beginning October 2013. The problem, of course, is that ICD-10-CM is geared for DSM IV, not for DSM-5. By good fortune, however, the time line for ICD-10-CM coincided precisely with the original time lines for DSM-5 so that there would be ample opportunity for the ICD-10-CM system to be customized for DSM-5, as it had been for DSM IV. If DSM 5 had been prepared on time, the ICD-10-CM coding system would have been able to incorporate the new disorders, subtypes, and specifiers being planned for it.

But the DSM 5 delays have likely greatly reduced or completely foreclosed this opportunity. In order to provide the coding community and insurers with a stable draft of the ICD-10-CM to allow programming of computer systems, the NCHS has imposed a two-year freeze on ICD-10-CM changes starting October 2011. The only exceptions are for new diseases arising within the two year period (eg the next new viral illness). The window of opportunity for making changes to ICD-10-CM has largely been closed and DSM 5, being so late to the gate, is pretty much left out in the cold. Its only remaining hope is that it will be able to convince NCHS that some of its proposed conditions are so compellingly new that they should fall under the exception to the freeze.

How did we get into this fix? Simple. Because DSM 5 is at least two years behind its original deadlines and was forever falling behind its own schedules, it has not been able to make final decisions that should certainly have been accomplished by now. As a result, the DSM 5 leadership will at best convince NHCS to get last minute unique ICD-10-CM codes for only a fraction of the DSM-5 proposals. The two-year delay in DSM-5 has closed a window that would have been open if things were done properly and on time. Had either the original May 2011 schedule (or even the one-year-late May 2012 deadline) been kept, APA's approval process would have coincided with the ICD-10-CM development process, resulting in a coding system that would have reflected the new changes. Instead, DSM-5 will be hobbled, having to contort its coding assignments to fit into an ICD-10-CM that was geared instead toward DSM IV.