Fwd: NYS Advisory to psychiatrists re: the use of antipsychotic medications

[Guest guest]

ALLIANCE FOR HUMAN RESEARCH PROTECTION Promoting Openness, Full Disclosure, and Accountabilityhttp://www.ahrp.org and http://ahrp.blogspot.com FYIThe legitimacy of psychiatry's clinical practices is unraveling as a copiousbody of evidence-documented in state / federal Medicaid records; in studiesthat compare the effects of drugs to placebo; in retrospective analyses ofmedical records, death reports, and internal company documents uncoveredduring product liability litigation-reveals that the drugs psychiatristsprescribe are harming rather than helping patients. After decades of denial,psychiatry is confronted with mounting evidence demonstrating that theso-called new 'atypical' antipsychotic drugs are seriously underminingpatients' physical and mental health and shortening lives. These drugs areat the subject of heated debate, government investigation, and masslitigation. A 2007 meta-analysis found: "In recent decades, the differential mortalitygap associated with schizophrenia has been increasing.compared with thegeneral population, people with schizophrenia have a 2- to 3-fold increasedrisk of dying.the potential [exists] for an even greater disease burden as aresult of the introduction of second-generation antipsychotic medications."[1] http://archpsyc.ama-assn.org/cgi/content/abstract/64/10/1123  Indeed,numerous studies have shown that these drugs are toxic to the heart: theyinduce arrhythmias and the metabolic syndrome which increases the risk ofdeath from coronary heart disease, as well as diabetes, hyperglycemia, andstroke. [2] [3] A report in The New England Journal of Medicine (2009) [4]http://content.nejm.org/cgi/content/short/360/3/225  finally prompted theNew York State Office of Mental Health (NYS OMH) to issue an advisory topsychiatrists (Feb 16, 2009) on the use of antipsychotic medications foradult patients. For the first time, OMH acknowledges: "There is mounting evidence, now reported in a variety of journals and thepopular press, that:. there are neither clear nor consistent distinctions in the clinicaleffectiveness between first and second generation APs (with clozapine theexception). there are cardiometabolic risks associated with specific first andsecond generation antipsychotics . there are risks for neurologic extrapyramidal side effects withspecific APs, particularly the higher potency first generation APs . there is a small risk of sudden cardiac death associated with APs The NEJM report by a Vanderbilt University team of physicians,pharmacologists, and epidemiologists-including a rheumatologist andcardiologist-is a comprehensive study that analyzed the Tennessee Medicaiddata (Jan 1, 1990 to Dec. 31, 2005) for adults aged 30 to 74. They confinedthe analysis to current users of antipsychotic drugs,  93,300  (44,218 wereprescribed a typical (older) antipsychotic and 46,089 were prescribed an'atypical' antipsychotic. Nonusers of antipsychotic drugs numbered 186,600.Typical antipsychotics prescribed: Haldol (haloperidol) and Thorazine(thioridazine). Atypical antipsychotics prescribed: Clozaril (clozapine),Zyprexa (olanzapine), Seroquel (quetiapine) and Risperdal (risperidone).The researchers matched users and nonusers (according to the predictedprobability that a person would be a user of antipsychotic drugs) andcompared the incidence of sudden cardiac death. The findings are clear andunequivocal: "Current users of typical and of atypical antipsychotic drugshad higher rates of sudden cardiac death than did nonusers of antipsychoticdrugs." http://content.nejm.org/cgi/content/short/360/3/225  An editorial in the same issue of the NEJM (excerpt below) [5] by twoprominent Harvard expert pharmacoepidemiologists, Sebastian Schneeweiss,M.D., Sc.D., and Jerry Avorn, M.D., commends the Vanderbilt team for theirespecially "well designedcomprehensive" study which "accuratelyrepresents events that happen shortly after initiation of therapy." Persuaded by the evidence demonstrating the significant risk for cardiacdeath from antipsychotics, Drs. Schneeweiss and Avorn advocate sharpreductions in the use of antipsychotics for off-label indications-inparticular for children and the elderly. "In the absence of clearlyestablished benefits.the risk of a fatal side effect is not likely to beacceptable."  They recommend establishing a risk-management program to protect patients,noting such a program has been in place for two decades to monitor forreduction in white blood cells in patients taking clozapine. The rate ofdeath due to clozapine-induced agranulocytosis was 0.2 per 1,000 patientyears. Whereas the risk of sudden cardiac death from antipsychotics, theynote, was substantially higher: 2.9 deaths per 1,000 patient years at lowdose, and 3.3 deaths per 1,000 at high dose.  Their reasonable recommendation: "if an antipsychotic agent is necessary, it seems reasonable to obtain anelectrocardiogram before and shortly after initiation of treatment with anantipsychotic drug. This modest effort could enable each patient starting ona high-dose antipsychotic to be screened for existing or emergentprolongation of the QT interval."http://content.nejm.org/cgi/content/full/360/3/294 The OMH advisory is accompanied by a Guidance document issued by theAmerican Psychiatric Association (APA) authored by Dr. Jeffrey Lieberman,Chairman of Psychiatry, Columbia University and Director of the NYSPsychiatric Institute. The APA Guidance demonstrates psychiatry's fierceresistance to evidence-based medicine.http://www.omh.state.ny.us/omhweb/advisories/adult_antipsychotic_use_attachement.htmlDr. Lieberman questions the validity of the Vanderbilt study using obtusearguments and a tortured line of reasoning that is all but unintelligible.  He acknowledges that the old antipsychotics are associated with suddencardiac death, but denies the evidence showing that the much more widelyprescribed, atypical antipsychotics pose at least double the risk of death.The following statement encapsulates psychiatry's disregard for evidence:"the finding that second-generation agents were associated with a comparablerisk was new information and surprising as the newer medications have beenconsidered to be generally safer."The evidence, however, shows that the risk of cardiac death is slightlyhigher for patients prescribed an atypical: The incidence-ratio "among usersof typical antipsychotic drugs increased from 1.31 (range: 0.97 to 1.77) forthose taking low doses to 2.42 (1.91 to 3.06) for those taking high doses(P<0.001). Among users of atypical agents, the incidence-rate ratiosincreased from 1.59 (1 .03 to 2.46) for those taking low doses to 2.86 (2.25to 3.65) for those taking high doses (P=0.01). Dr. Lieberman was a leading investigator in the government sponsored,schizophrenia effectiveness study, CATIE (2005) [6] which found nodifference in effectiveness between the old and new antipsychotics, butdocumented profound harm produced by the atypicals. Dr. Lieberman, et alreported that: 64% to 70% of patients in the CATIE study (number ofpatients, 1,460, mean age, 40) suffered "moderate to severe" adverse events;74% dropped out; and 3% of patients who were treated with Risperdal andSeroquel had prolongation of the QT interval. [5, see, Table 3]  Drs. Schneeweiss and Avorn note: "It is striking that it took so long to establish the elevated riskassociated with atypical antipsychotic medications given that the firstagent in this class (clozapine) entered the U.S. market in 1989."  Theanswer is psychiatry has not been guided by the "do no harm" principle ofmedicine, nor has it adhered to scientific standards of objectivity. For two decades, psychiatry's leadership enthusiastically promoted thesedrugs in journal articles, at professional conferences, and continuingmedical education courses as "safer and more effective" than the oldneuroleptics. Prominent academic psychiatrists persuaded colleagues that thedrugs were safe to use for untested, unapproved, off-label conditions andfor vulnerable children and the elderly. Their careers and substantialsource of extra income are invested in promoting the delusion that the drugsare "safe and effective."The OMH advisory does not recommend a reduction in the use of these drugs,declaring: "Antipsychotic medications remain a mainstay in the effectivetreatment of psychotic illnesses." And Dr. Lieberman, writing on behalf ofthe APA, rejects the safeguards recommended by Drs. Schneeweiss and Avorn:"Instituting a policy of routine serial measurement of the QTc interval inall patients initiating treatment with antipsychotic medication may bepremature." http://www.omh.state.ny.us/omhweb/advisories/adult_antipsychotic_use_attachement.htmlSudden cardiac death is not the only dose-related, potentially lethalcardiovascular risk linked to the atypicals. The drugs interfere with normal metabolic function inducing a cascade oflife-threatening risks which increase mortality among users. A meta-analysis of 37 studies in the Archives of General Psychiatry (2007)[1] documented a widening gap in the standardized mortality rate betweenpatients with schizophrenia and the general population.  The authors suggestthat the mortality rate they calculated "captures only a fraction of theeventual burden of mortality associated with the adverse effect profile ofthe second generation antipsychotic medications." They found:"compared with typical antipsychotics, several of the second-generationantipsychotics are more likely to cause weight gain and metabolic syndrome.Because the metabolic syndrome is associated with a 2-to 3-fold increase incardiovascular mortality and a 2-fold increase in all-cause mortality, theseadverse effects would be expected to contribute to even higher mortalityrates in the next few decades."  Furthermore, "Adverse health outcomesassociated with weight gain and/or metabolic syndrome (eg, myocardialinfarction, cerebrovascular accidents, or cancer) may take decades to fullyemerge." http://archpsyc.ama-assn.org/cgi/content/abstract/64/10/1123 In light of the multiple, cumulative debilitating and fatal risks posed byantipsychotics, and "the absence of clearly established benefits," thesedrugs are unacceptable for use--except in crisis situations for shortduration. But psychiatry's practices are governed by neither humanitarian medicine,nor evidence-based medicine. The profession denies the scientific evidenceand the drug-induced deteriorating condition of their patients--some of whogain more than 125 lbs develop diabetes and cardiovascular illnesses.Psychiatrists cling to a self-perpetuating delusion, the belief that thedrugs they prescribe are "well tolerated, safe and effective" when theevidence clearly shows them not to be either. Psychiatry has a professionaland financial investment in promoting the belief that its treatments aresuccessful: "The reputed success of psychiatric drug treatments has beenfoundational to the efforts of psychiatrists to elevate their field's statuswithin the medical community." [7] Pity the patients who are condemned to the ministrations of uncaring andunyielding professionals who cling to a failed, inhumane paradigm of carethat undermines patients'  health, increases suffering, and shortens theirlives."They shoot horses, don't they?"References:1. Sukanta Saha, MSc, MCN; David Chant, PhD; John McGrath, MD, PhD,FRANZCP A Systematic Review of Mortality in Schizophrenia: Is theDifferential Mortality Gap Worsening Over Time? Arch Gen Psychiatry.2007;64(10):1123-1131http://archpsyc.ama-assn.org/cgi/content/abstract/64/10/1123 2. Joukamaa M, et al. Schizophrenia, neuroleptic medication andmortality, British J of Psychiatry, 2006;188:122-127. 3. See, numerous studies cited by Moncrieff J. in The Myth of theChemical Cure: A Critique of Psychiatric Drug Treatment, 2008, PalgraveMacmillan.4. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypicalantipsychotic drugs and the risk of sudden cardiac death. NEJM 2009;360:225-235.5. Sebastian Schneeweiss, M.D., Sc.D., and Jerry Avorn, M.D.Antipsychotic Agents and Sudden Cardiac Death -How Should We Manage theRisk?  NEJM 2009, 360:294-6.6. Lieberman JA, Stroup S, McEvoy JP, et al. Effectiveness ofAntipsychotic Drugs in Patients with Chronic Schizophrenia, NEJM 2005;353:1209-23. 7. Horowitz A. Book Review, NEJM 2009; 360:841-44.Contact: Vera Hassner Sharavveracare212-595-8974http://www.omh.state.ny.us/omhweb/advisories/adult_antipsychotic_use.html OMH Advisory On Antipsychotic Medication Use In AdultsLloyd I. Sederer, MDMedical DirectorFebruary 16, 2009Dear Colleague,This OMH Advisory is on the use of antipsychotic medications (APs) for adultpatients served by the New York State Office of Mental Health. We hope thesecomments will be of value to others in the mental health community.There is mounting evidence, now reported in a variety of journals and thepopular press, that:* although there are differences between individual AP drugs there areneither clear nor consistent distinctions in the clinical effectivenessbetween first and second generation APs (with the exception of clozapine) asclasses of drugs * there are significant risks of prescribing APs to individuals withdementia - See OMH Advisory.<http://www.omh.state.ny.us/omhweb/advisories/advisory_fda_antipsychotic.htm * there are cardiometabolic risks associated with specific first andsecond generation APs * there are risks for neurologic extrapyramidal side effects withspecific APs, particularly the higher potency first generation APs * there is a small risk of sudden cardiac death associated with APs All medications carry risks (and have side effects). The work of prescribingclinicians is to identify benefit and risk and help patients make informeddecisions about their health and treatment. Antipsychotic medications remain a mainstay in the effective treatment ofpsychotic illnesses thereby calling for even greater care regarding whichagent we recommend to each individual patient - and what monitoring weprovide before and during the course of treatment. Recall, as well, that therisk of relapse is far greater in people with psychotic illness if they donot take APs - as noted in OMH Advisory on APs<http://www.omh.state.ny.us/omhweb/advisories/antipsychotic_medications.html . Recent concerns about the risk of sudden cardiac death in people taking APsled the American Psychiatric Association (APA) to issue the attachedguidance document<http://www.omh.state.ny.us/omhweb/advisories/adult_antipsychotic_use_attachement.html> . This release comes from the APA Council on Research, chairedby Dr. Jeffrey Lieberman, the Director of the New York State PsychiatricInstitute and Chair of Psychiatry at Columbia. The OMH Medical Director's office is working with Dr. Lieberman on atemplate to provide guidance to each OMH prescribing clinician to review theAP medications of all their patients. We envision a decision tree forexisting patients at the time of their next appointment and for all newpatients. This is a complex endeavor and one that warrants the carefulthought of experts, which we have undertaken. We hope that this work alsowill be useful to colleagues outside of the OMH.As you see your patients, please be sure to continue to consider benefit,risk, side effects, drug-drug interactions, the lowest doses possible foreffectiveness, and the importance of psychosocial treatments for allpatients who meet indications for the prescription of an AP medication (orany medication for that matter).We welcome your comments.Please feel free to distribute this material to your colleagues.Sincerely, Lloyd I. Sederer, MDMedical Director, NYS Office of Mental Health-----------<http://www.omh.state.ny.us/omhweb/advisories/adult_antipsychotic_use_attachement.html#ft>APA Guidance on the Use of Antipsychotic Drugs and Cardiac Sudden DeathPrepared by Jeffrey A. Lieberman, M.D., David Merrill, M.D., and SharatParameswaran, M.D.  for the APA Council on ResearchIn the January 15, 2009, issue of the New England Journal of Medicine, WayneA. Ray, PhD, and colleagues reported findings of a study investigating therisk of sudden cardiac death (SCD) associated with the use of antipsychoticmedications (Ray et al., 2009). The researchers used a Tennessee Medicaiddatabase to retrospectively calculate the incidence of SCD among 44,218users of typical (i.e. first-generation) agents, 46,089 users of atypical(i.e. second-generation) agents and 186,600 nonusers of antipsychotic drugs.The patients included in the study were 30 to 74 years of age, andpredominantly women, white and residing in urban areas. The individual drugsthat were analyzed were haloperidol, thioridazine, clozapine, olanzapine,quetiapine and risperidone.Ray and colleagues found that both antipsychotic classes were associatedwith an approximate doubling of the risk of SCD, relative to the baselinerate among nonusers of antipsychotics. In absolute terms, the incidence ofSCD among patients prescribed antipsychotics was approximately three eventsper 1000 patient-years. This risk was dose-dependent in both medicationclasses, with doses equivalent to 300 mg or more of chlorpromazine per dayposing the greatest risk. That first-generation antipsychotics are associated with SCD is wellestablished (Ray et al., 2001; Straus et al., 2004), but the finding thatsecond-generation agents were associated with a comparable risk was newinformation and surprising as the newer medications have been considered tobe generally safer. Careful examination of the study methodology, however, raises questionsabout the validity of the results. Ray and colleagues used a retrospectiveanalysis of death certificates to evaluate mortality by SCD, which mayoverestimate SCD incidence. Multiple studies using a prospective,multiple-source surveillance method (Chugh et al., 2004; Byrne et al., 2008;Vaillancourt et al., 2004) have shown rates of SCD in the general populationbetween 51 and 56 per 100,000 person-years, compared to 143 per 100,000person-years in the study by Ray and colleagues. A direct comparison betweenthe prospective and retrospective methods showed a positive predictive valueof only 19% with the latter method (Chugh et al., 2004). In addition, Rayand colleagues utilized an unvalidated cardiovascular risk score to assesspatients' risk for SCD, noting a non-significantly lower baseline risk scorein patients receiving antipsychotic medications than in those not receivingthem. This finding is inconsistent with existing evidence regarding highrates of cardiovascular morbidity and mortality in patients with mentalillness, particularly severe mental illness (Newcomer et al, 2007; Osborn etal., 2006; Goff et al., 2005). Indeed, a lower calculated cardiovascularrisk in patients taking antipsychotic medication may actually reflect thewell-known low rates of detection and treatment of cardiovascular riskfactors in patients with mental illness (Nasrallah et al., 2006), which mayaccount for the higher rate of cardiac-related mortality among antipsychoticusers in this study. Neither cardiovascular risk nor primary mental illnesswas controlled for in the primary cohorts analyzed by Ray and colleagues; asecondary set of cohorts, while better matched for mental illness,specifically excluded patients with schizophrenia. Without controlling forthese potentially confounding variables, it is unclear whether the highrates of cardiac mortality reported in this study were attributable toantipsychotic medications or other causes.Ray and colleagues suggested that the most likely mechanism of SCD amongantipsychotic users is a drug-induced blockade of repolarizing currents incardiac myocytes, leading to a prolongation of the electrocardiogram (ECG)rate-corrected QT interval (QTc), and ultimately to the potentially fatalventricular tachyarrhythmia torsades de pointes (TdP). An accompanyingeditorial (Schneeweiss and Avorn, 2009) proposed that an ECG be obtainedbefore and shortly after initiation of treatment with an antipsychotic drug.According to the editorial, when QT interval prolongation is detected, theantipsychotic dose should be reduced or the drug discontinued, other riskfactors for SCD should be addressed, and follow-up ECGs should be obtained.Instituting a policy of routine serial measurement of the QTc interval inall patients initiating treatment with antipsychotic medication may bepremature. While some antipsychotics are known to substantially prolong theQTc, others do so to only a modest degree (Harrigan et al., 2004).Furthermore, although prolongation of the QTc is the best available clinicalsurrogate for the development of TdP, it is an imperfect biomarker (Shah,2005; Sager, 2008). The QTc generally has low specificity for predictingarrhythmias, and for some drugs a dissociation exists between QTcprolongation and TdP risk (Sager, 2008).Given the methodological limitations of the study by Ray and colleagues, andthe lack of data regarding the utility and cost-effectiveness of serial QTcmeasurement in antipsychotic-treated patients, clinicians should continue toobserve extant practice guidelines for the work-up and management ofpsychotic patients. With regard to cardiac safety, these include obtaining amedical and medication history, a thorough physical exam, vital signs androutine laboratory tests (APA, 2006). Thioridazine, mesoridazine andpimozide should not be prescribed for patients with cardiac risk factors ofknown heart disease, a personal history of syncope, a family history ofsudden death under age 40, or prolonged QTc syndrome (Marder et al., 2004).If these agents are prescribed, serum potassium and an ECG should be checkedbefore drug initiation; serum potassium and an ECG should also be checked inthe presence of the above cardiac risk factors prior to treatment withziprasidone (APA, 2004). An ECG should be checked again following asignificant change in dose of thioridazine, mesoridazine, pimozide or, inthe presence of cardiac risk factors, ziprasidone, or following the additionof another QTc-prolonging medication (APA, 2004), or if a patient presentswith symptoms associated with a prolonged QTc interval (e.g., syncope)(Marder et al., 2004). An absolute QTc interval of >500 msec or an increaseof 60 msec from baseline may be associated with an increased risk of TdP(Haddad and Anderson, 2002) and should prompt reduction or discontinuationof the offending agent.When prescribing antipsychotic medication, clinicians are encouraged to usethe lowest dose effective for any given patient in order to minimizedose-dependent adverse effect risks.~~~~~~~~~~~~~~~~~  Antipsychotic Agents and Sudden Cardiac Death -How Should We Manage theRisk?Sebastian Schneeweiss, M.D., Sc.D., and Jerry Avorn, M.D.NEJM 2-9, 360:294-6.It is striking that it took so long to establish the elevated riskassociated with atypical antipsychoticmedications given that the first agent in this class (clozapine) entered theU.S. marketin 1989. Ray et al. present a comprehensive study that makes a clear casefor the increased risk ofsudden cardiac death associated with all antipsychotic drugs. Their researchhas all the attributesof a well-designed pharmacoepidemiologic study; many of these attributesseem obvious but aretoo often poorly implemented. The authors confine their analysis to newusers of the studydrugs; this design accurately represents events that happen shortly afterthe initiation of therapy,events that could otherwise be underestimated by including the greaterperson-time contributedby long-term users (or "survivors") of the drug, who may be less susceptibleto the outcomethat is being studied.7 They also establish a clear temporal sequencebetween patient characteristicsbefore the initiation of treatment and the outcomes after initiation.Sudden cardiac death can be a difficult end point to capture in databases ofhealth care use.Ray et al. developed and tested an algorithm that combined information fromdeath certificateswith data on health care use. This algorithm resulted in a positivepredictive value of 86%,which would result in only minor underestimation of risk.Should the use of antipsychotic medications be restricted on the basis ofthese data? Much of their use is in vulnerable populations and outside thelabeled indications, including the use in children and in the elderly withdementia,1,2 and there is much less evidence of efficacy in thesepopulations. In the absence of clearly established benefits for many ofthese patients, the risk of a fatal side effect is not likely to beacceptable. For these patients, the use of antipsychotic medications shouldbe reduced sharply, perhaps by requiring an age-dependent justification fortheir use.FAIR USE NOTICE: This may contain copyrighted (C ) material the use of whichhas not always been specifically authorized by the copyright owner. Suchmaterial is made available for educational purposes, to advanceunderstanding of human rights, democracy, scientific, moral, ethical, andsocial justice issues, etc. It is believed that this constitutes a 'fairuse' of any such copyrighted material as provided for in Title 17 U.S.C.section 107 of the US Copyright Law. This material is distributed withoutprofit. _____________Infomail1 mailing listto send a message to Infomail1-leave =====In accordance with Title 17 U.S.C. Section 107, this material is distributed without profit to those who have expressed a prior interest in receiving the included information for research and educational purposes.

[Guest guest]

thanks

 

 

On 2/25/09, Viviane Lerner <vivlerner wrote:

>

>

>

>

> ALLIANCE FOR HUMAN RESEARCH PROTECTION

> Promoting Openness, Full Disclosure, and Accountability

> http://www.ahrp.org and http://ahrp.blogspot.com

>

> FYI

> The legitimacy of psychiatry's clinical practices is unraveling as a

> copious

> body of evidence-documented in state / federal Medicaid records; in

> studies

> that compare the effects of drugs to placebo; in retrospective

> analyses of

> medical records, death reports, and internal company documents uncovered

> during product liability litigation-reveals that the drugs psychiatrists

> prescribe are harming rather than helping patients. After decades of

> denial,

> psychiatry is confronted with mounting evidence demonstrating that the

> so-called new 'atypical' antipsychotic drugs are seriously undermining

> patients' physical and mental health and shortening lives. These

> drugs are

> at the subject of heated debate, government investigation, and mass

> litigation.

>

> A 2007 meta-analysis found: " In recent decades, the differential

> mortality

> gap associated with schizophrenia has been increasing.compared with the

> general population, people with schizophrenia have a 2- to 3-fold

> increased

> risk of dying.the potential [exists] for an even greater disease

> burden as a

> result of the introduction of second-generation antipsychotic

> medications. "

> [1] http://archpsyc.ama-assn.org/cgi/content/abstract/64/10/1123

> Indeed,

> numerous studies have shown that these drugs are toxic to the heart:

> they

> induce arrhythmias and the metabolic syndrome which increases the

> risk of

> death from coronary heart disease, as well as diabetes,

> hyperglycemia, and

> stroke. [2] [3]

>

> A report in The New England Journal of Medicine (2009) [4]

> http://content.nejm.org/cgi/content/short/360/3/225 finally prompted

> the

> New York State Office of Mental Health (NYS OMH) to issue an advisory to

> psychiatrists (Feb 16, 2009) on the use of antipsychotic medications for

> adult patients. For the first time, OMH acknowledges:

>

> " There is mounting evidence, now reported in a variety of journals

> and the

> popular press, that:

> . there are neither clear nor consistent distinctions in the clinical

> effectiveness between first and second generation APs (with clozapine

> the

> exception)

> . there are cardiometabolic risks associated with specific first and

> second generation antipsychotics

> . there are risks for neurologic extrapyramidal side effects with

> specific APs, particularly the higher potency first generation APs

> . there is a small risk of sudden cardiac death associated with APs

>

> The NEJM report by a Vanderbilt University team of physicians,

> pharmacologists, and epidemiologists-including a rheumatologist and

> cardiologist-is a comprehensive study that analyzed the Tennessee

> Medicaid

> data (Jan 1, 1990 to Dec. 31, 2005) for adults aged 30 to 74. They

> confined

> the analysis to current users of antipsychotic drugs, 93,300

> (44,218 were

> prescribed a typical (older) antipsychotic and 46,089 were prescribed an

> 'atypical' antipsychotic. Nonusers of antipsychotic drugs numbered

> 186,600.

> Typical antipsychotics prescribed: Haldol (haloperidol) and Thorazine

> (thioridazine). Atypical antipsychotics prescribed: Clozaril

> (clozapine),

> Zyprexa (olanzapine), Seroquel (quetiapine) and Risperdal (risperidone).

>

> The researchers matched users and nonusers (according to the predicted

> probability that a person would be a user of antipsychotic drugs) and

> compared the incidence of sudden cardiac death. The findings are

> clear and

> unequivocal: " Current users of typical and of atypical antipsychotic

> drugs

> had higher rates of sudden cardiac death than did nonusers of

> antipsychotic

> drugs. " http://content.nejm.org/cgi/content/short/360/3/225

>

> An editorial in the same issue of the NEJM (excerpt below) [5] by two

> prominent Harvard expert pharmacoepidemiologists, Sebastian Schneeweiss,

> M.D., Sc.D., and Jerry Avorn, M.D., commends the Vanderbilt team for

> their

> especially " well designed " " comprehensive " study which " accurately

> represents events that happen shortly after initiation of therapy. "

>

> Persuaded by the evidence demonstrating the significant risk for cardiac

> death from antipsychotics, Drs. Schneeweiss and Avorn advocate sharp

> reductions in the use of antipsychotics for off-label indications-in

> particular for children and the elderly. " In the absence of clearly

> established benefits.the risk of a fatal side effect is not likely to be

> acceptable. "

>

> They recommend establishing a risk-management program to protect

> patients,

> noting such a program has been in place for two decades to monitor for

> reduction in white blood cells in patients taking clozapine. The rate of

> death due to clozapine-induced agranulocytosis was 0.2 per 1,000 patient

> years. Whereas the risk of sudden cardiac death from antipsychotics,

> they

> note, was substantially higher: 2.9 deaths per 1,000 patient years at

> low

> dose, and 3.3 deaths per 1,000 at high dose.

> Their reasonable recommendation:

> " if an antipsychotic agent is necessary, it seems reasonable to

> obtain an

> electrocardiogram before and shortly after initiation of treatment

> with an

> antipsychotic drug. This modest effort could enable each patient

> starting on

> a high-dose antipsychotic to be screened for existing or emergent

> prolongation of the QT interval. "

> http://content.nejm.org/cgi/content/full/360/3/294

>

> The OMH advisory is accompanied by a Guidance document issued by the

> American Psychiatric Association (APA) authored by Dr. Jeffrey

> Lieberman,

> Chairman of Psychiatry, Columbia University and Director of the NYS

> Psychiatric Institute. The APA Guidance demonstrates psychiatry's fierce

> resistance to evidence-based medicine.

> http://www.omh.state.ny.us/omhweb/advisories/

> adult_antipsychotic_use_attache

> ment.html

>

> Dr. Lieberman questions the validity of the Vanderbilt study using

> obtuse

> arguments and a tortured line of reasoning that is all but

> unintelligible.

> He acknowledges that the old antipsychotics are associated with sudden

> cardiac death, but denies the evidence showing that the much more widely

> prescribed, atypical antipsychotics pose at least double the risk of

> death.

> The following statement encapsulates psychiatry's disregard for

> evidence:

> " the finding that second-generation agents were associated with a

> comparable

> risk was new information and surprising as the newer medications have

> been

> considered to be generally safer. "

>

> The evidence, however, shows that the risk of cardiac death is slightly

> higher for patients prescribed an atypical: The incidence-ratio

> " among users

> of typical antipsychotic drugs increased from 1.31 (range: 0.97 to

> 1.77) for

> those taking low doses to 2.42 (1.91 to 3.06) for those taking high

> doses

> (P<0.001). Among users of atypical agents, the incidence-rate ratios

> increased from 1.59 (1 .03 to 2.46) for those taking low doses to

> 2.86 (2.25

> to 3.65) for those taking high doses (P=0.01).

>

> Dr. Lieberman was a leading investigator in the government sponsored,

> schizophrenia effectiveness study, CATIE (2005) [6] which found no

> difference in effectiveness between the old and new antipsychotics, but

> documented profound harm produced by the atypicals. Dr. Lieberman, et al

> reported that: 64% to 70% of patients in the CATIE study (number of

> patients, 1,460, mean age, 40) suffered " moderate to severe " adverse

> events;

> 74% dropped out; and 3% of patients who were treated with Risperdal and

> Seroquel had prolongation of the QT interval. [5, see, Table 3]

>

> Drs. Schneeweiss and Avorn note:

> " It is striking that it took so long to establish the elevated risk

> associated with atypical antipsychotic medications given that the first

> agent in this class (clozapine) entered the U.S. market in 1989. " The

> answer is psychiatry has not been guided by the " do no harm "

> principle of

> medicine, nor has it adhered to scientific standards of objectivity.

> For two decades, psychiatry's leadership enthusiastically promoted these

> drugs in journal articles, at professional conferences, and continuing

> medical education courses as " safer and more effective " than the old

> neuroleptics. Prominent academic psychiatrists persuaded colleagues

> that the

> drugs were safe to use for untested, unapproved, off-label conditions

> and

> for vulnerable children and the elderly. Their careers and substantial

> source of extra income are invested in promoting the delusion that

> the drugs

> are " safe and effective. "

>

> The OMH advisory does not recommend a reduction in the use of these

> drugs,

> declaring: " Antipsychotic medications remain a mainstay in the effective

> treatment of psychotic illnesses. " And Dr. Lieberman, writing on

> behalf of

> the APA, rejects the safeguards recommended by Drs. Schneeweiss and

> Avorn:

> " Instituting a policy of routine serial measurement of the QTc

> interval in

> all patients initiating treatment with antipsychotic medication may be

> premature. " http://www.omh.state.ny.us/omhweb/advisories/adult_

> antipsychotic_use_attachement.html

>

> Sudden cardiac death is not the only dose-related, potentially lethal

> cardiovascular risk linked to the atypicals.

> The drugs interfere with normal metabolic function inducing a cascade of

> life-threatening risks which increase mortality among users.

> A meta-analysis of 37 studies in the Archives of General Psychiatry

> (2007)

> [1] documented a widening gap in the standardized mortality rate between

> patients with schizophrenia and the general population. The authors

> suggest

> that the mortality rate they calculated " captures only a fraction of the

> eventual burden of mortality associated with the adverse effect

> profile of

> the second generation antipsychotic medications. "

>

> They found:

> " compared with typical antipsychotics, several of the second-generation

> antipsychotics are more likely to cause weight gain and metabolic

> syndrome.

> Because the metabolic syndrome is associated with a 2-to 3-fold

> increase in

> cardiovascular mortality and a 2-fold increase in all-cause

> mortality, these

> adverse effects would be expected to contribute to even higher mortality

> rates in the next few decades. " Furthermore, " Adverse health outcomes

> associated with weight gain and/or metabolic syndrome (eg, myocardial

> infarction, cerebrovascular accidents, or cancer) may take decades to

> fully

> emerge. "

> http://archpsyc.ama-assn.org/cgi/content/abstract/64/10/1123

>

> In light of the multiple, cumulative debilitating and fatal risks

> posed by

> antipsychotics, and " the absence of clearly established benefits, " these

> drugs are unacceptable for use--except in crisis situations for short

> duration.

>

> But psychiatry's practices are governed by neither humanitarian

> medicine,

> nor evidence-based medicine. The profession denies the scientific

> evidence

> and the drug-induced deteriorating condition of their patients--some

> of who

> gain more than 125 lbs develop diabetes and cardiovascular illnesses.

> Psychiatrists cling to a self-perpetuating delusion, the belief that the

> drugs they prescribe are " well tolerated, safe and effective " when the

> evidence clearly shows them not to be either. Psychiatry has a

> professional

> and financial investment in promoting the belief that its treatments are

> successful: " The reputed success of psychiatric drug treatments has been

> foundational to the efforts of psychiatrists to elevate their field's

> status

> within the medical community. " [7]

>

> Pity the patients who are condemned to the ministrations of uncaring and

> unyielding professionals who cling to a failed, inhumane paradigm of

> care

> that undermines patients' health, increases suffering, and shortens

> their

> lives.

>

> " They shoot horses, don't they? "

>

> References:

> 1. Sukanta Saha, MSc, MCN; David Chant, PhD; John McGrath, MD, PhD,

> FRANZCP A Systematic Review of Mortality in Schizophrenia: Is the

> Differential Mortality Gap Worsening Over Time? Arch Gen Psychiatry.

> 2007;64(10):1123-1131

> http://archpsyc.ama-assn.org/cgi/content/abstract/64/10/1123

> 2. Joukamaa M, et al. Schizophrenia, neuroleptic medication and

> mortality, British J of Psychiatry, 2006;188:122-127.

> 3. See, numerous studies cited by Moncrieff J. in The Myth of the

> Chemical Cure: A Critique of Psychiatric Drug Treatment, 2008, Palgrave

> Macmillan.

> 4. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical

> antipsychotic drugs and the risk of sudden cardiac death. NEJM 2009;

> 360:225-235.

> 5. Sebastian Schneeweiss, M.D., Sc.D., and Jerry Avorn, M.D.

> Antipsychotic Agents and Sudden Cardiac Death -How Should We Manage the

> Risk?

> NEJM 2009, 360:294-6.

> 6. Lieberman JA, Stroup S, McEvoy JP, et al. Effectiveness of

> Antipsychotic Drugs in Patients with Chronic Schizophrenia, NEJM 2005;

> 353:1209-23.

> 7. Horowitz A. Book Review, NEJM 2009; 360:841-44.

>

>

> Contact: Vera Hassner Sharav

> veracare

> 212-595-8974

>

>

> http://www.omh.state.ny.us/omhweb/advisories/

> adult_antipsychotic_use.html

> OMH Advisory On Antipsychotic Medication Use In Adults

> Lloyd I. Sederer, MD

> Medical Director

> February 16, 2009

>

> Dear Colleague,

>

> This OMH Advisory is on the use of antipsychotic medications (APs)

> for adult

> patients served by the New York State Office of Mental Health. We

> hope these

> comments will be of value to others in the mental health community.

>

> There is mounting evidence, now reported in a variety of journals and

> the

> popular press, that:

> * although there are differences between individual AP drugs there are

> neither clear nor consistent distinctions in the clinical effectiveness

> between first and second generation APs (with the exception of

> clozapine) as

> classes of drugs

> * there are significant risks of prescribing APs to individuals with

> dementia - See OMH Advisory.

> <http://www.omh.state.ny.us/omhweb/advisories/

> advisory_fda_antipsychotic.htm

>>

> * there are cardiometabolic risks associated with specific first and

> second generation APs

> * there are risks for neurologic extrapyramidal side effects with

> specific APs, particularly the higher potency first generation APs

> * there is a small risk of sudden cardiac death associated with APs

>

> All medications carry risks (and have side effects). The work of

> prescribing

> clinicians is to identify benefit and risk and help patients make

> informed

> decisions about their health and treatment.

>

> Antipsychotic medications remain a mainstay in the effective

> treatment of

> psychotic illnesses thereby calling for even greater care regarding

> which

> agent we recommend to each individual patient - and what monitoring we

> provide before and during the course of treatment. Recall, as well,

> that the

> risk of relapse is far greater in people with psychotic illness if

> they do

> not take APs - as noted in OMH Advisory on APs

> <http://www.omh.state.ny.us/omhweb/advisories/

> antipsychotic_medications.html

>> .

>

> Recent concerns about the risk of sudden cardiac death in people

> taking APs

> led the American Psychiatric Association (APA) to issue the attached

> guidance document

> <http://www.omh.state.ny.us/omhweb/advisories/

> adult_antipsychotic_use_attach

> ement.html> . This release comes from the APA Council on Research,

> chaired

> by Dr. Jeffrey Lieberman, the Director of the New York State Psychiatric

> Institute and Chair of Psychiatry at Columbia.

>

> The OMH Medical Director's office is working with Dr. Lieberman on a

> template to provide guidance to each OMH prescribing clinician to

> review the

> AP medications of all their patients. We envision a decision tree for

> existing patients at the time of their next appointment and for all new

> patients. This is a complex endeavor and one that warrants the careful

> thought of experts, which we have undertaken. We hope that this work

> also

> will be useful to colleagues outside of the OMH.

>

> As you see your patients, please be sure to continue to consider

> benefit,

> risk, side effects, drug-drug interactions, the lowest doses possible

> for

> effectiveness, and the importance of psychosocial treatments for all

> patients who meet indications for the prescription of an AP

> medication (or

> any medication for that matter).

>

> We welcome your comments.

> Please feel free to distribute this material to your colleagues.

>

> Sincerely,

> Lloyd I. Sederer, MD

> Medical Director, NYS Office of Mental Health

>

> -----------

>

> <http://www.omh.state.ny.us/omhweb/advisories/

> adult_antipsychotic_use_attach

> ement.html#ft>

> APA Guidance on the Use of Antipsychotic Drugs and Cardiac Sudden Death

> Prepared by Jeffrey A. Lieberman, M.D., David Merrill, M.D., and Sharat

> Parameswaran, M.D. for the APA Council on Research

>

> In the January 15, 2009, issue of the New England Journal of

> Medicine, Wayne

> A. Ray, PhD, and colleagues reported findings of a study

> investigating the

> risk of sudden cardiac death (SCD) associated with the use of

> antipsychotic

> medications (Ray et al., 2009). The researchers used a Tennessee

> Medicaid

> database to retrospectively calculate the incidence of SCD among 44,218

> users of typical (i.e. first-generation) agents, 46,089 users of

> atypical

> (i.e. second-generation) agents and 186,600 nonusers of antipsychotic

> drugs.

> The patients included in the study were 30 to 74 years of age, and

> predominantly women, white and residing in urban areas. The

> individual drugs

> that were analyzed were haloperidol, thioridazine, clozapine,

> olanzapine,

> quetiapine and risperidone.

>

> Ray and colleagues found that both antipsychotic classes were associated

> with an approximate doubling of the risk of SCD, relative to the

> baseline

> rate among nonusers of antipsychotics. In absolute terms, the

> incidence of

> SCD among patients prescribed antipsychotics was approximately three

> events

> per 1000 patient-years. This risk was dose-dependent in both medication

> classes, with doses equivalent to 300 mg or more of chlorpromazine

> per day

> posing the greatest risk.

>

> That first-generation antipsychotics are associated with SCD is well

> established (Ray et al., 2001; Straus et al., 2004), but the finding

> that

> second-generation agents were associated with a comparable risk was new

> information and surprising as the newer medications have been

> considered to

> be generally safer.

>

> Careful examination of the study methodology, however, raises questions

> about the validity of the results. Ray and colleagues used a

> retrospective

> analysis of death certificates to evaluate mortality by SCD, which may

> overestimate SCD incidence. Multiple studies using a prospective,

> multiple-source surveillance method (Chugh et al., 2004; Byrne et

> al., 2008;

> Vaillancourt et al., 2004) have shown rates of SCD in the general

> population

> between 51 and 56 per 100,000 person-years, compared to 143 per 100,000

> person-years in the study by Ray and colleagues. A direct comparison

> between

> the prospective and retrospective methods showed a positive

> predictive value

> of only 19% with the latter method (Chugh et al., 2004). In addition,

> Ray

> and colleagues utilized an unvalidated cardiovascular risk score to

> assess

> patients' risk for SCD, noting a non-significantly lower baseline

> risk score

> in patients receiving antipsychotic medications than in those not

> receiving

> them. This finding is inconsistent with existing evidence regarding high

> rates of cardiovascular morbidity and mortality in patients with mental

> illness, particularly severe mental illness (Newcomer et al, 2007;

> Osborn et

> al., 2006; Goff et al., 2005). Indeed, a lower calculated cardiovascular

> risk in patients taking antipsychotic medication may actually reflect

> the

> well-known low rates of detection and treatment of cardiovascular risk

> factors in patients with mental illness (Nasrallah et al., 2006),

> which may

> account for the higher rate of cardiac-related mortality among

> antipsychotic

> users in this study. Neither cardiovascular risk nor primary mental

> illness

> was controlled for in the primary cohorts analyzed by Ray and

> colleagues; a

> secondary set of cohorts, while better matched for mental illness,

> specifically excluded patients with schizophrenia. Without

> controlling for

> these potentially confounding variables, it is unclear whether the high

> rates of cardiac mortality reported in this study were attributable to

> antipsychotic medications or other causes.

>

> Ray and colleagues suggested that the most likely mechanism of SCD among

> antipsychotic users is a drug-induced blockade of repolarizing

> currents in

> cardiac myocytes, leading to a prolongation of the electrocardiogram

> (ECG)

> rate-corrected QT interval (QTc), and ultimately to the potentially

> fatal

> ventricular tachyarrhythmia torsades de pointes (TdP). An accompanying

> editorial (Schneeweiss and Avorn, 2009) proposed that an ECG be obtained

> before and shortly after initiation of treatment with an

> antipsychotic drug.

> According to the editorial, when QT interval prolongation is

> detected, the

> antipsychotic dose should be reduced or the drug discontinued, other

> risk

> factors for SCD should be addressed, and follow-up ECGs should be

> obtained.

>

> Instituting a policy of routine serial measurement of the QTc

> interval in

> all patients initiating treatment with antipsychotic medication may be

> premature. While some antipsychotics are known to substantially

> prolong the

> QTc, others do so to only a modest degree (Harrigan et al., 2004).

> Furthermore, although prolongation of the QTc is the best available

> clinical

> surrogate for the development of TdP, it is an imperfect biomarker

> (Shah,

> 2005; Sager, 2008). The QTc generally has low specificity for predicting

> arrhythmias, and for some drugs a dissociation exists between QTc

> prolongation and TdP risk (Sager, 2008).

>

> Given the methodological limitations of the study by Ray and

> colleagues, and

> the lack of data regarding the utility and cost-effectiveness of

> serial QTc

> measurement in antipsychotic-treated patients, clinicians should

> continue to

> observe extant practice guidelines for the work-up and management of

> psychotic patients. With regard to cardiac safety, these include

> obtaining a

> medical and medication history, a thorough physical exam, vital signs

> and

> routine laboratory tests (APA, 2006). Thioridazine, mesoridazine and

> pimozide should not be prescribed for patients with cardiac risk

> factors of

> known heart disease, a personal history of syncope, a family history of

> sudden death under age 40, or prolonged QTc syndrome (Marder et al.,

> 2004).

> If these agents are prescribed, serum potassium and an ECG should be

> checked

> before drug initiation; serum potassium and an ECG should also be

> checked in

> the presence of the above cardiac risk factors prior to treatment with

> ziprasidone (APA, 2004). An ECG should be checked again following a

> significant change in dose of thioridazine, mesoridazine, pimozide

> or, in

> the presence of cardiac risk factors, ziprasidone, or following the

> addition

> of another QTc-prolonging medication (APA, 2004), or if a patient

> presents

> with symptoms associated with a prolonged QTc interval (e.g., syncope)

> (Marder et al., 2004). An absolute QTc interval of >500 msec or an

> increase

> of 60 msec from baseline may be associated with an increased risk of TdP

> (Haddad and Anderson, 2002) and should prompt reduction or

> discontinuation

> of the offending agent.

>

> When prescribing antipsychotic medication, clinicians are encouraged

> to use

> the lowest dose effective for any given patient in order to minimize

> dose-dependent adverse effect risks.

> ~~~~~~~~~~~~~~~~~

>

> Antipsychotic Agents and Sudden Cardiac Death -How Should We Manage the

> Risk?

> Sebastian Schneeweiss, M.D., Sc.D., and Jerry Avorn, M.D.

> NEJM 2-9, 360:294-6.

>

> It is striking that it took so long to establish the elevated risk

> associated with atypical antipsychotic

> medications given that the first agent in this class (clozapine)

> entered the

> U.S. market

> in 1989. Ray et al. present a comprehensive study that makes a clear

> case

> for the increased risk of

> sudden cardiac death associated with all antipsychotic drugs. Their

> research

> has all the attributes

> of a well-designed pharmacoepidemiologic study; many of these attributes

> seem obvious but are

> too often poorly implemented. The authors confine their analysis to new

> users of the study

> drugs; this design accurately represents events that happen shortly

> after

> the initiation of therapy,

> events that could otherwise be underestimated by including the greater

> person-time contributed

> by long-term users (or " survivors " ) of the drug, who may be less

> susceptible

> to the outcome

> that is being studied.7 They also establish a clear temporal sequence

> between patient characteristics

> before the initiation of treatment and the outcomes after initiation.

>

> Sudden cardiac death can be a difficult end point to capture in

> databases of

> health care use.

> Ray et al. developed and tested an algorithm that combined

> information from

> death certificates

> with data on health care use. This algorithm resulted in a positive

> predictive value of 86%,

> which would result in only minor underestimation of risk.

>

> Should the use of antipsychotic medications be restricted on the

> basis of

> these data? Much of their use is in vulnerable populations and

> outside the

> labeled indications, including the use in children and in the elderly

> with

> dementia,1,2 and there is much less evidence of efficacy in these

> populations. In the absence of clearly established benefits for many of

> these patients, the risk of a fatal side effect is not likely to be

> acceptable. For these patients, the use of antipsychotic medications

> should

> be reduced sharply, perhaps by requiring an age-dependent

> justification for

> their use.

>

>

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> of which

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>

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