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The Food and Drug Administration (FDA) today approved Invega (paliperidone) extended-release tablets for the treatment of schizophrenia. Paliperidone is a new molecular entity, which means this medication contains an active substance that has never before been approved for marketing in any form in the United States. Paliperidone is the principal active metabolite of risperidone, a marketed drug for treating schizophrenia.
"Schizophrenia can be a devastating illness requiring lifelong medication and professional counseling," said Douglas Throckmorton, MD, Deputy Director of FDA's Center for Drug Evaluation and Research. "Today's approval adds to the treatment options for patients with this condition."
Schizophrenia is a chronic, disabling mental disorder that affects more than two million Americans. Symptoms include hallucinations, delusions, disordered thinking, movement disorders, social withdrawal and cognitive deficits (e.g., difficulty with perception, memory or abstract thinking that interferes with one's ability to learn; impaired judgment, inattentiveness, impulsiveness or impairment of speech and language).
The effectiveness of Invega in the acute treatment of schizophrenia was established in three 6-week, placebo-controlled trials conducted in North America, Europe and Asia. The 1665 participating adults were evaluated for the full array of signs and symptoms of schizophrenia. In the three studies using doses ranging from three milligrams (mg) to 15 mg a day, the effectiveness of Invega at relieving symptoms of schizophrenia was superior to the placebo treatment. The recommended dose range for Invega is three mg to 12 mg a day.
Among the commonly reported adverse events were restlessness, extrapyramidal symptoms (movement disorders), rapid heart beat and sleepiness. Invega is a member of a class of drugs called atypical antipsychotics that have an increased rate of death compared with placebo in elderly patients with dementia-related psychosis. Invega is not approved for dementia-related psychosis.
The effectiveness of Invega has not been evaluated in placebo-controlled trials for longer than six weeks, and patients who use the drug for extended periods should be periodically reevaluated by a physician.
Invega is manufactured by ALZA Corp. in Mountain View, CA. for Janssen, L.P. in Titusville, NJ.
PRINCETON, N.J., and TOKYO, Dec. 12 /PRNewswire-FirstCall/ -- Bristol-Myers Squibb Company (NYSE: BMY) and Otsuka Pharmaceutical Co., Ltd. today announced the launch of ABILIFY® (aripiprazole) Injection, an injectable form of ABILIFY, for intramuscular use. ABILIFY Injection provides rapid control of agitation in adults with schizophrenia or bipolar mania at primary endpoint (2 hours). The U.S. Food and Drug Administration (FDA) approved ABILIFY Injection on September 20, 2006.
The urgent nature of acute agitation requires immediate assessment and intervention. ABILIFY Injection provides healthcare professionals with the first ready-to-use single-dose vial (9.75 mg/1.3 mL) of an atypical antipsychotic to calm the agitated patient.
"Acute agitation can be very serious, distressing and potentially dangerous for patients, healthcare professionals and caregivers," said Michael H. Allen, MD, Director, Emergency Psychiatry, Associate Professor, University of Colorado at Denver and Health Sciences Center's School of Medicine. "ABILIFY Injection controls agitation independent of sedation."
Fonte: http://newsroom.bms.com (Bristol - Otsuka)
Am J Psychiatry 163:2080-2089, December 2006
doi: 10.1176/appi.ajp.163.12.2080
© 2006 American Psychiatric Association
NATIONAL INSTITUTE of MENTAL HEALTH (United States)
The public may reproduce without permission information from the National Institute of Mental Health website, except for documents that state another copyright policy applies to them. Restrictions on the reproduction of a document may arise if a private party has sponsored it. The NIMH, however, is the sole sponsor of most of the information on his site)
December 1, 2006
Contact: Colleen Labbe
NIMH Press Office
301-443-4536
NIMHpress@nih.gov
A new study analyzing the economic implications of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) concludes that the older (first generation) antipsychotic medication perphenazine was less expensive and no less effective than the newer (second generation) medications used in the trial during initial treatment, suggesting that older antipsychotics still have a role in treating schizophrenia. The study, published in the American Journal of Psychiatry on December 1, 2006, was funded by the National Institutes of Health's National Institute of Mental Health (NIMH).
The $42.6 million CATIE trial aimed to help doctors and the 2.4 million Americans who suffer from chronic schizophrenia tailor treatments to individual needs. It is the first study to directly compare several second generation antipsychotic medications and a representative first generation antipsychotic medication.
"The results from CATIE should encourage doctors to reconsider the use of perphenazine as another choice for patients with schizophrenia," said NIMH Director Thomas Insel, M.D.
More than 90 percent of antipsychotic prescriptions are written for second generation medications, despite the fact they are more expensive than the first generation agents used to treat schizophrenia. The majority of clinicians have traditionally believed that the newer antipsychotics are more effective and better tolerated than older agents, and many experts argued that these advantages justified the difference in cost.
Robert Rosenheck, M.D., of Yale University, and colleagues analyzed costs and quality-of-life factors associated with each of the five medications used in Phase 1 of the CATIE trial—olanzapine, quietapine, risperidone, ziprasidone, and perphenazine. They found that total monthly health costs, a figure that includes both average medication costs and inpatient and outpatient costs, were up to 30 percent lower for those taking the perphenazine than for those taking the second generation medications. In addition, the researchers found no statistically significant difference in overall effectiveness between perphenazine and the second generation antipsychotics, with regard to symptom relief and side effect burden.
The findings echo what was implied in the results of the first phase of CATIE, expanding the treatment options for patients with schizophrenia. It casts doubt on the notion that the second generation antipsychotics are better than the first generation antipsychotics, and suggests that perphenazine and other first generation antipsychotics may be just as beneficial for some patients.
Still, several conditions of CATIE limit any firm conclusions about perphenazine's perceived advantages. Not all patients respond the same to different medications. In addition, the study lasted 18 months—long enough to determine how patients respond to and initially tolerate the drugs, but not long enough to consider some serious long-term side effects, such as development of the movement disorder tardive dyskinesia (TD), diabetes, cardiovascular problems, or other medical conditions that can develop even years after a patient with chronic schizophrenia starts taking an antipsychotic medication. Despite these caveats, the study results suggest new ways of thinking about medication treatments for schizophrenia.
"These results encourage doctors to revisit the older medication as an alternative, especially if a treatment change is warranted," said Dr. Rosenheck. "By showing that perphenazine and possibly other older antipsychotics may be on equal footing with the second generation antipsychotics, CATIE has opened the door to more choice in treatment options."
The National Institute of Mental Health (NIMH) mission is to reduce the burden of mental and behavioral disorders through research on mind, brain, and behavior. More information is available at the NIMH website. The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
Rosenheck RA, Leslie DL, Sindelar J, Miller EA, Lin H, Stroup TS, McEvoy J, Davis S, Keefe R, Swartz M, Perkins D, Hsiao JK, Lieberman J. Cost-effectiveness of Second Generation Antipsychotics and Perphenazine in a Randomized Trial of Treatment for Chronic Schizophrenia. American Journal of Psychiatry. 2006 Dec;163 (12): 2080-89.
The recent publication (December 1, 2006, American Journal of Psychiatry) of the cost-effectiveness results from the National Institute of Mental Health (NIMH)-funded Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) has raised questions among advocates, families, and clinicians about reimbursement policies for antipsychotic medications.
Antipsychotics have now become the fourth largest group of medications prescribed in the United States, with a collective cost expected to surge past $10 billion this year. About 80 percent of the prescriptions for antipsychotics are paid via the public sector. The new atypical medications, representing 90 percent of the current market, are approximately 10 times the cost of the older conventional antipsychotics.
In a report in the September 22, 2005, New England Journal of Medicine, the CATIE research team compared discontinuation rates with four atypical antipsychotics (olanzapine, quetiapine, risperidone, ziprasidone) and one older conventional antipsychotic (perphenazine). The results demonstrated few differences overall among the various medications. The older medication, perphenazine, was as well tolerated as the newer compounds and as effective as three of the four newer drugs. The fourth compound, olanzapine, was slightly better than all the others in terms of discontinuation and hospitalization rates but was also associated with higher rates of weight gain and metabolic side effects.
The December 1, 2006 study analyzed the economic implications of the CATIE results and found that, because perphenazine was as effective overall and less expensive, the older antipsychotic medications such as perphenazine still have a valuable role in treating schizophrenia. The results should encourage doctors to reconsider the use of these older medications as another choice for patients with schizophrenia. This study should help expand the current list of medications most commonly used for schizophrenia, rather than restrict or reduce access to any of the antipsychotic medications. NIMH believes that this is important for the following reasons:
Although the CATIE results suggest little difference in the overall effectiveness for the entire cohort, individual patients respond differently to different medications. To say the medications are equivalent is not to say they are identical. There is substantial variability in the response of individuals to these treatments. Future studies will focus on predicting individual patterns of response.
There are additional outcomes to consider. Upcoming reports will describe the effectiveness of these various medications on quality of life and cognitive deficits. Cognitive impairment is a central clinical feature of schizophrenia and is strongly associated with functional outcomes.
CATIE was limited to people with chronic schizophrenia who were moderately treatment-resistant. People with acute, first onset schizophrenia and those with other psychotic disorders were not included in this study. These patients may respond differently to antipsychotic medications.
CATIE was an 18-month study. While this is longer than most clinical trials it is not long enough to fully consider whether patients would develop serious long-term side effects such as tardive dyskinesia, diabetes, or other medical conditions that can develop even years after starting medication.
Taking all these points into consideration, NIMH holds that families and physicians need more, not fewer, choices for addressing schizophrenia. A one-size-fits-all approach for treating schizophrenia could be harmful, essentially turning the clock back 40 years to an era when conventional antipsychotics were the only medications available for patients with this chronic, disabling disorder affecting 3.2 million Americans.
Schizophr Research. 2006 Dec;88(1-3):5-25. Epub 2006 Aug 23.
Pharmacological treatment of primary negative symptoms in schizophrenia: A systematic review.
Murphy BP, Chung YC, Park TW, McGorry PD.
ORYGEN Youth Health, Melbourne, Victoria, Australia; Department of Psychiatry, University of Melbourne, Victoria, Australia.
BACKGROUND: Optimal treatment of primary negative symptoms is important because their presence is associated with poor outcome. AIMS: To systematically review all studies dealing with the efficacy of pharmacological agents on primary negative symptoms. METHOD: A comprehensive search of the relevant literature was undertaken using electronic database, reference lists and personal contact. RESULTS: There is a lack of standardized research designs. Amisulpride is the most extensively studied drug with respect to efficacy against primary negative symptoms. At low doses it demonstrates a consistent, modest effect compared to placebo, though not to conventional antipsychotics and has yet to be tested against other atypicals. Evidence from multiple studies that used simple statistical analyses and inclusion criteria for patients with primary negative symptoms does not support a direct effect for clozapine. Path-analysis studies support the direct effects of risperidone, olanzapine, sertindole and aripiprazole, however, different statistical analyses of the same risperidone study produced conflicting results and the direct effects of olanzapine were not confirmed in selected patients with primary negative symptoms. There are no studies supporting the use of ziprasidone or quetiapine. The effects of typical antipsychotics on primary negative symptoms are inconclusive and likely to depend on drug dosages. Selective serotonin reuptake inhibitors (SSRIs), mirtazepine and NMDA agonists show early promise but require further study. Novel agents such as selegiline, naltrexone, dehydroepiandrosterone, galantamine, Ginkgo, nitric oxide, l-deprenyl and pergolide show positive effects on general negative symptoms but remain untested against primary negative symptoms. CONCLUSIONS: Further studies using standardized selective inclusion criteria and controlling for chronicity are needed. Research guidelines are discussed.
Six-Month Study Evaluated Effectiveness of Aripiprazole and Standard of Care In Management of Community-Treated Patients with Schizophrenia
- Data Presented at the 159th Annual Meeting of the American Psychiatric Association -
TORONTO, May 25 /PRNewswire-FirstCall/ -- The Bristol-Myers Squibb Company (NYSE: BMY) and Otsuka Pharmaceutical Co., Ltd. atypical antipsychotic medicine, aripiprazole, demonstrated significantly greater improvement on the Investigator's Assessment Questionnaire (IAQ) versus standard-of-care in a six-month, randomized, open-label, multicenter trial of more than 500 adults living with schizophrenia conducted in Europe.(1) The IAQ is a validated instrument that is a combined measure of efficacy, safety and tolerability, and is composed of 10 items.(2) Standard-of-care included treatment with one of the following atypical antipsychotics: olanzapine, quetiapine or risperidone.
The data are from a study called STAR (Schizophrenia Trial of ARipiprazole), performed in community-based treatment settings. The findings, presented today at the 159th Annual Meeting of the American Psychiatric Association (APA), also reported the effects of aripiprazole and standard-of- care on changes in metabolic measures, including weight and blood lipids,(3) and change in sexual dysfunction.(4)
Details of the STAR Trial
In the STAR Trial, 555 adults with schizophrenia whose clinical symptoms were not optimally controlled or who experienced tolerability problems with their current medication were randomized to either aripiprazole (10-30 mg/day) or one of three standard-of-care therapies: olanzapine (5-20 mg/day), quetiapine (100-800 mg/day) or risperidone (2-8 mg/day, up to 16 mg/day). The choice of standard-of-care was based on physician discretion; the results from subjects on a standard-of-care therapy were analyzed and reported as one group.
The IAQ Total Score is the sum of 10 items: positive symptoms, negative symptoms, somnolence, weight gain, signs and symptoms of prolactin elevation, akathisia, extrapyramidal symptoms (EPS), cognition, energy and mood. A lower score correlates generally with an improvement in the combined measure of efficacy, safety and tolerability.
One presentation of the STAR data (abstract NR929)(1) at APA reported that at Week 26, the mean IAQ Total Score was significantly lower for adults taking aripiprazole compared with standard-of-care: 25.7 vs. 27.7 (p-value less than 0.001), respectively. Similar results were reported for the mean change in Clinical Global Impression Improvement (CGI-I) score for aripiprazole and standard-of-care. A greater proportion of aripiprazole-treated adults were rated by the investigator as "very much improved" or "much improved" based on the CGI-I scale: 44 percent aripiprazole vs. 34 percent standard-of-care (p-value equals 0.009). Adverse events occurring in at least 5 percent of adults taking aripiprazole and a greater rate than standard-of-care were: nausea (10.6% vs. 1.1%), akathisia (8.9% vs. 2.3%), headache (13.5% vs. 7.9%), agitation (5.0% vs. 1.9%), anxiety (16.0% vs. 11.3%), insomnia (24.1% vs. 7.5%) and psychotic disorder (7.4% vs. 4.9%). Adverse events occurring in at least 5 percent of the adults taking standard-of-care and a greater rate than aripiprazole were: fatigue (6.0% vs. 3.5%), weight increase (9.4% vs. 1.1%), somnolence (11.7% vs. 3.9%) and schizophrenia (6.4% vs. 6.0%).
Another STAR-based presentation (abstract NR391)(3) at APA reported mean changes from baseline in levels of total cholesterol, HDL-C, LDL-C, triglycerides, glucose and weight. After 26 weeks of treatment with aripiprazole or standard-of-care, respectively, results demonstrated a mean change in total cholesterol plasma levels (-20.3 mg/dL vs. -7.7 mg/dL, p-value less than 0.001), HDL-C (+2.0 mg/dL vs. +0.4 mg/dL, p-value equals 0.028), LDL-C (-13.3 mg/dL vs. -5.8 mg/dL, p-value less than 0.001), triglycerides (-46.3 mg/dL vs. -13.0 mg/dL, p-value less than 0.001), weight (-1.3 kg vs. +2.1 kg, p-value less than 0.001) and glucose levels (+0.2 mg/dL vs. +3.3 mg/dL, p-value equals 0.146, not significant).
Results reported in abstract NR361(4) at APA included mean change from baseline in the Arizona Sexual Experience Scale (ASEX) Total Score. The ASEX is a 5-item scale to evaluate sexual dysfunction among psychiatric patients. A lower score correlates with improvement in sexual function. At Week 26, mean change from baseline in ASEX Total Score for each treatment group was -1.44 plus or minus 0.31 for aripiprazole and -0.56 plus or minus 0.34 for standard- of-care (p-value equals 0.012).
A fourth presentation (abstract NR360)(5) at APA described the major reasons healthcare professionals decided to change their patients' treatment regimen to enter the STAR study, which included the presence of negative symptoms (71%), lack of energy (59.3%), the presence of positive symptoms (50.6%), cognitive impairment (44.7%), weight gain (39.3%), somnolence (34%), mood (34.1%), extrapyramidal symptoms (19.6%) and signs and symptoms of prolactin elevation (12.4%).
Kerwin R, L'Italien G, Hanssens L, Marcus R, McQuade R, Carson W,
Beuzen J-N, for the STAR Study Group. Effectiveness of aripiprazole
versus standard of care: Schizophrenia Trial of Aripiprazole: STAR
Trial. Poster presentation at the 159th annual meeting of the
American Psychiatric Association, Abstract NR929, May 20-25, 2006.
Department of Psychiatry,Woodhull Medical and Mental Health Center, Brooklyn, New York, USA
Correspondence: Dr Robertt E. McCue, Department of Psychiatry, Wooodhull Medical and Mental Health Center, 760 Broadway, Brooklyn, New York 11206,USA. Email: mccuer@nychhc.org
See editorial, pp. 391–392, this issue.
Background There is little information on the comparative effectiveness of second-generation antipsychotic agents.
Aims To determine if any of five second-generation antipsychotics or haloperidolis more effective in treating acutely ill patients with schizophrenia, schizoaffective disorder or schizophreniform disorder.
Method A sample of 327 newly admitted patients were randomised to open-label treatment with aripiprazole, haloperidol, olanzapine, quetiapine, risperidone or ziprasidone for a minimum of 3 weeks. Measures of effectiveness were improvement in mental status so that the patient no longer required acute in-patient care, and changes in Brief Psychiatric Rating Scale (BPRS) scores.
Results By the first measure, haloperidol (89%), olanzapine (92%) and risperidone (88%) were significantly more effective than aripiprazole (64%), quetiapine (64%) and ziprasidone (64%). Changes in BPRS ratings were not significant among treatments.
Conclusions Haloperidol, olanzapine and risperidone are superior to aripiprazole, quetiapine and ziprasidone for the acute treatment of psychosis in hospitalised patients with schizophrenia, schizoaffective disorder or schizophreniform disorder.
The British Journal of Psychiatry (2006) 189: 391-392. doi: 10.1192/bjp.bp.106.029983
© 2006 The Royal College of Psychiatrists
EDITORIAL
Correspondence: Professor Clive E. Adams, Co-ordinating Editor, Cochrane Schizophrenia Group, University of Leeds, 15 Hyde Terrace, Leeds LS2 9LT, UK. Tel: +44 (0)113 343 1965; fax: +44 (0)113 343 2723; email: ceadams@cochrane-sz.org
Declaration of interest T.S.S. has consulted for Janssen and consulted and spoken for Lilly and Pfizer; he is a principal investigator in a Schizophrenia Trials Network, sponsored by the National Institute of Mental Health, aiming to undertake pragmatic randomised trials.
See pp. 433–440, this issue.
Most people with schizophrenia live in low- and middle-income countries in which clinicians/policy makers are not the first targets of marketing. Because it is years after a drug is first launched that the full effects become known with confidence, the evidence upon which to base practice in low- and middle-income countries may be less biased than that in richer nations.
Encephale. 2006 Jul-Aug;32(4 Pt 1):446-51
Biological models of schizophrenia: an update [Article in French]
Lotstra F.
Service de Psychiatrie, Hopital Erasme, 808, route de Lennik, 1070 Bruxelles.
This paper is a review of the principal, currently proposed, biological models of schizophrenia. The convergence of recent neurobiological studies indicates that schizophrenia may be a neurodevelopmental and progressive disorder with multiple biochemical abnormalities involving dopamine, serotonin, glutamate and gamma-aminobutyric acidergic systems. In post-mortem tissue, structural abnormalities and alterations in synaptic connectivity have been observed in the intracortical circuitry of the prefrontal dorsal cortex. These morphological modifications could be sequelae of earlier environmental insults and genetic processes. There are probably multiple susceptibility genes, each of small effect, which act in conjunction with environmental factors: obstetric abnormalities, intra-uterine infection and abnormal nutrition. Candidate identified genes could influence neurodevelopment, synaptic plasticity and neurotransmission. If schizophrenia is clearly related to an abnormality of early brain development, the clinical expression of the illness itself is delayed typically for about two decades after birth. A similar delayed onset is also observed in the secondary psychosis associated with metachromatic leukodystrophy, a genetic disease affecting myelin. Schizophrenia is a term reserved for idiopathic cases of chronic psychosis. Strictly speaking, schizophrenia is a syndrome. There are no established laboratory tests, neuro-imaging studies, electrophysiological paradigms or neuropsychological testing batteries that can explicitly confirm this behavioural disorder to the exclusion of symptomatology: what physicians diagnose as schizophrenia today may prove to be a cluster of different illnesses, with similar and overlapping symptoms. The diagnosis criteria of the various DSM reflect the American psychiatrists' concern for establishing a consensus classification preserving a wider definition of schizophrenia or more precisely of the schizophrenic disorder. One can presume that research work established from too numerous and insufficiently specific variables doesn't permit the definition of one or several aetiologies. We hope that one day all schizophrenia will be correlated to one precise causal factor permitting the optimal targeting of interesting therapeutic approaches. The multiplicity of concepts and models reflects our questioning.
PMID: 17099555 [PubMed - indexed for MEDLINE]
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Schizophrenia Research
Volume 88, Issues 1-3 , December 2006, Pages 127-134
Copyright © 2006 Elsevier B.V. All rights reserved.
Long-term outcomes in chronically hospitalized geriatric patients with schizophrenia: Retrospective comparison of first generation and second generation antipsychotics
Leonard White Joseph I. Friedman, Christopher R. Bowie, Martin Evers, Philip D. Harvey, Michael Parrella, Emilian Mihaila and Kenneth L. Davis
aClinical Neuroscience Center, Pilgrim Psychiatric Center, West Brentwood, NY, USA
bDepartment of Psychiatry, Mt Sinai School of Medicine, New York, NY, USA
Received 24 February 2006; revised 23 June 2006; accepted 26 June 2006. Available online 22 August 2006.
Abstract
Introduction
Some groups have reported the longitudinal course of elderly poor outcome schizophrenic patients to be characterized by progressive decline in cognitive functions and functional capacity. Although many of these patients experience minimal reduction of psychotic symptoms, there may be beneficial effects of antipsychotic treatments on cognitive functions and functional capacity.
Methods
This naturalistic study compared the longitudinal course of psychotic symptoms, cognitive functions and functional impairment in geriatric schizophrenic patients treated with first generation (N = 97) or second generation (N = 78) antipsychotic medications. Mixed effects linear regression analyses were used to examine the effects of treatment (first generation vs. second generation antipsychotic), time and treatment × time.
Results
Cognitive functions (Mini Mental State Examination time effect estimate = − .41, p < .001; ADAS-L Cog time effect estimate = .64, p < .001) and self-care skills (ADAS-L Self-Care time effect estimate = .65, p < .001) declined over time for the subject group as a whole and this decline was not modified by treatment with second generation antipsychotics relative to first generation antipsychotics. Similarly, second generation antipsychotic treatment produced no effect on the progressive worsening of negative symptom over time.
Conclusion
This long-term naturalistic study of poor outcome geriatric patients with schizophrenia did not find atypical antipsychotics to produce any differential protective effect relative to typical antipsychotics on the long-term manifestations of symptoms, cognition and self-care in poor outcome geriatric schizophrenic patients.
Keywords: Schizophrenia; Geriatric; Antipsychotic; Cognition
Earlier versions of this paper were presented at the Mt. Sinai Cognition Conference, Savannah, Georgia, March 31–April 1, 2005 and XX International Conference on Schizophrenia Research Savannah, Georgia, April 2–April 6, 2005.
This work was supported by grant number P50 MH 66392-01 awarded by the NIMH to Kenneth Davis.
Corresponding author. Pilgrim Psychiatric Center, 998 Crooked Hill Road, Bldg 47, Brentwood, NY, 11717, USA. Tel.: +1 631 761 2144; fax: +1 631 761 2718.
1 Joseph I. Friedman, MD has a financial interest/relationship or affiliation in the form of: Grant Research Support from Eli Lilly and Company.
2 Philip D. Harvey, PhD has a financial interest/relationship or affiliation in the form of: Consultant for AstraZeneca Pharmaceuticals LP; Janssen Pharmaceutica Products LP; Eli Lilly and Company and Novartis Pharmaceuticals.
3 Kenneth L. Davis MD has a financial interest/ relationship or affiliation in the form of: Consultant for Janssen Pharmaceutica Products,
Am J Psychiatry 163:1481-1483, September 2006
doi: 10.1176/appi.ajp.163.9.1481
© 2006 American Psychiatric Association
The American Journal of Psychiatry
APA Steering Committee on Practice Guidelines
Psychiatric Services
Journal of Neuropsychiatry and Clinical Neurosciences
Focus
Psychiatric News
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Boston, Mass.
American Psychiatric Association
The editors of the Journal last commented on conflict of interest in an editorial in the April 2006 issue (1). Two recent incidents highlight the continuing level of professional and public concern over this issue.
The first incident arose when it was discovered that some of the authors of an article published in JAMA, in which the results of an NIMH-supported study of antidepressants in pregnancy were reported, did not disclose that they had received support for other activities from pharmaceutical companies. The editors of JAMA, as well as the general media, criticized their lack of full disclosure (2). For original research articles, as opposed to editorials and review articles, most journals have required disclosure of the funding source for the study but not disclosure of all other sources of income of each of the authors. The rationale was that the major influence on the conduct of a study comes from the funding source itself. For example, for the JAMA study, NIMH support signifies that there was independent peer review of the study design. Authors are always asked for "relevant" conflicts of interest, but perceptions of what is relevant when the study itself is funded by NIMH differ. Many people do not believe that they are influenced by pharmaceutical industry funding and therefore do not see a need for self-disclosure of other funding. However, as the reaction to the JAMA article illustrates, our credibility as a field requires complete disclosure of authors’ sources of income from the pharmaceutical and biomedical industry. The American Journal of Psychiatry now requires full disclosure of all industry-derived personal income and research funding from all authors for all articles. The disclosures will be published at the end of the article, beginning with the October issue. The article and these disclosures are reviewed by the editors for any evidence of bias as part of the decision for publication.
The second incident arose following a Wall Street Journal report that a Perspective published in Neuropsychopharmacology on vagus nerve stimulation did not fully disclose the relationship between its authors and the company that manufactures the stimulator (3). It is precisely because editorials and review articles often recommend treatment that we outlined in our April 2006 editorial that these submissions to The American Journal of Psychiatry would have broader disclosure requirements that include all sources of support.
Disclosure has been a concern of medical journals for the past decade. Medical journals depend on the voluntary compliance of authors. Lapses, intentional and unintentional, in adherence to disclosure guidelines may occur. The New York Times, in an editorial, called for sanctions against medical authors who commit egregious lapses (4). Journals do not have the capability to investigate and decide upon sanctions with due process for those accused of serious violations. Furthermore, multiple collaborations, which often include junior trainees, are common, and sanctions would result in the withdrawal of papers for one author’s actions that would cause harm to other careers. It has been suggested that medical schools through the American Association of Medical Colleges adopt uniform policies to deal with offenders (5). Medical schools, which are required to regulate conflict of interest by federal funding agencies, possess the appropriate investigative committee structures. A uniform standard applied to all academic investigators would strengthen the credibility of all of medicine.
What happens beyond disclosure? Failures in disclosure are problematic because we believe that pharmaceutical and other industrial support—through speakers’ honoraria, consultation fees, and research contracts—may bias the conduct of studies, the interpretation of data, and the reporting of findings (6). Such support may also influence the choice of treatments and other basic aspects of the practice of medicine. There is evidence that advertising promotion influences practice and that pharmaceutical companies target opinion leaders, including authors of articles in medical journals, precisely in order to influence practice (7). The ethical concerns of medical journal publishing and of medical practice generally coincide. We do not publish articles that violate patient confidentiality because we do not violate confidentiality in the practice of medicine. We require informed consent for treatment, and so we also require it for research papers. We do not allow boundary violations in either, and we require that all interventions, whether clinical or research, have beneficial intent. Given the absence of a standard for the influence of pharmaceutical companies in our practice, it is not surprising that we do not have one for our journals. Indeed, the journals would seem to be ahead of medical practice, since most of us do not disclose to our patients the extent to which we have had interactions with the companies from whom we ask them to buy their medications (8).
Complete separation from the pharmaceutical industry is not the answer. We cannot practice optimally without prescribing medications and without being fully informed about them. Those of us who do research intend that our findings will lead to better treatment, including better medications that pharmaceutical companies will ultimately manufacture, test, register, and market. However, new ethical standards and clearer boundaries are needed. Because we do not have a consensus among us for what constitutes good behavior, we are vulnerable to those who criticize our profession for any form of relationship with the pharmaceutical industry.
Ethical standards for the practice of medicine and for research are constantly evolving. It is timely for this evolution to include pharmaceutical company influences. One of the leaders is the Accreditation Council for Continuing Medical Education, which now has strict requirements, not only for speakers’ disclosure of conflicts of interest, but also for their independence from any influence in the preparation of their articles, slides, and talks.
Asserting control of our own education might be a first goal for us and for our professional organizations. Ethical behavior might include individual decisions by physicians to refuse marketing gifts, including trips and meals in company-sponsored educational programs. Professional societies might examine participation in speakers’ bureaus to see if it fulfills the requirements of an ethical activity for its members. Medical schools may wish to consider whether it is an appropriate activity for faculty members. The result might be that medical journals would have less conflict of interest to disclose, since fewer authors would receive income closely tied to the marketing efforts of pharmaceutical companies.
At the same time, we need to recognize the legitimacy of some activities. Consultation with the pharmaceutical industry for meaningful research and clinical purposes, not just for marketing goals, needs to continue to ensure that the enormous investment of the pharmaceutical companies in the development of new drugs is spent for the best purposes. The participation of academic researchers in clinical trials should be enhanced, not weakened, as an important source of independent judgment in the assessment of new drugs. The companies also have a legitimate role in their support of the education of physicians, both through financial support of medical education and through their marketing programs. For example, marketing through advertising in independent professional journals such as this one, where promotion material is clearly separated from the educational content, has long been considered ethical. We need to continue to define and to enforce the boundaries between promotional activities, including advertising, and the presentation of clinical and scientific information free from bias.
The public concern over the JAMA article is a reminder that anything that undermines public confidence in the medical profession also undermines public acceptance of recommended drug treatments. For psychopharmaceuticals in particular, the public’s perception that medications are prescribed by physicians free from industry influence is critical. Thus, just as we need to establish boundaries for our ethical behavior, the pharmaceutical industry needs to use its industrial organizations to set new boundaries and standards for the ethical support of physician education. We cannot allow treatment of our vulnerable patients to be compromised because of the unintended effects of overly zealous marketing.
Our previous editorial was a statement of policy for our Journal, signed by its editors. Conflict of interest has developed beyond an issue for medical journals into an issue that now affects our field as a whole. Therefore, we have sought to develop a wider, although certainly not complete, consensus, which is reflected in the expanded authorship below
March 23, 2006
Contact: NIMH Press Office
NIMH Press Office
301-443-4536
NIMHpress@nih.gov
Results of the nation's largest depression study show that one in three depressed patients who previously did not achieve remission using an antidepressant became symptom-free with the help of an additional medication and one in four achieved remission after switching to a different antidepressant. The study, funded by the National Institutes of Health's National Institute of Mental Health (NIMH), shows that people whose depression is resistant to initial treatment can achieve remission — the virtual absence of symptoms — when treated with a secondary strategy that either augments or switches medications. This is the first study to examine the effectiveness of different treatment strategies for those who did not become symptom-free after initial medication.
John Rush, M.D., and Madhukar H. Trivedi, M.D., of the University of Texas Southwestern Medical Center (UTSWMC), and colleagues report on the first major results of the clinical trial, known as the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study, in two papers published in the March 23, 2006 issue of the New England Journal of Medicine.
"These findings provide important treatment options to mental health clinicians and millions of Americans who struggle with treatment-resistant depression," said NIH Director Elias A. Zerhouni.
Patients who did not experience a remission of symptoms during the first level of the STAR*D study — in which they initially took the antidepressant citalopram, a selective serotonin reuptake inhibitor (SSRI) for up to 14 weeks — had the option of continuing to level 2 of the trial where they could explore additional treatment options designed to help them become symptom-free.
"If the first treatment attempt fails, patients should not give up," said NIMH's director Thomas Insel, M.D. "By remaining in treatment, and working closely with clinicians to tailor the most appropriate next steps, many patients may find the best single or combination treatment that will enable them to become symptom-free."
The 1,439 patients who were eligible and volunteered to enter level 2 were presented with seven different treatment options. Only very few participants said that all of the choices were equally acceptable and allowed themselves to be randomly assigned to any one of them. All the rest of the participants identified at least one of the treatments as being unacceptable, and chose to limit the treatments to which they would allow themselves to be randomly assigned. Fifty-one percent (727) of the patients chose options that included switching to a different medication and were randomly assigned to one of the three switch medications. Thirty-nine percent (565) chose options that included augmenting the citalopram they were already taking, and were randomly assigned to one of the two augmenting medications.
The 727 patients who received the switch medication treatments were randomized to take one of three medications currently available and used in practice — sertraline (an SSRI that targets the neurotransmitter serotonin), bupropion-SR (a non-SSRI antidepressant), or venlafaxine-XR (an agent that targets serotonin and norepinephrine, another neurotransmitter).
Rush and colleagues found that 25 percent of the patients who switched to a new medication became symptom-free within 14 weeks; this was similar within each of the three treatment groups. Additionally, no significant differences were found in the efficacy, safety or tolerability of the three medications to which patients were switched.
"Contrary to what previous research suggests, this study shows that all three medications the patients switched to, despite having different mechanisms of action, appear to be useful options for treating depression following failure on the first SSRI," said Rush. "The results provide patients and doctors with important information that intolerance or lack of efficacy with one SSRI seems not to predict the same with another."
The 565 patients who received the augment medication were randomized to take either bupropion-SR (a non-SSRI antidepressant) or buspirone (a medication that enhances the action of an SSRI) in addition to the SSRI citalopram that they were already taking in Level 1. Within 14 weeks of using either treatment, about one third of the patients who enrolled in the augmentation study became symptom-free, Trivedi and colleagues reported. Both combinations appeared similar in terms of remission; however, those who augmented citalopram with bupropion-SR experienced fewer symptoms, a greater degree of symptom relief and lower side effects compared to those who augmented with buspirone.
"Augmenting the first medication may be an effective way for people with depression to become symptom-free," said Trivedi. "Augmenting earlier in the course of treatment, or perhaps prescribing a combination of drugs to patients initially, may be more effective than using one treatment alone."
According to the researchers, the switch and augment treatments cannot be directly compared because of the way the trial was designed. The results, however, can be used to help guide treatment choices within each group; it also may be that different people respond better to one as opposed to another treatment.
"Further research may help customize the treatment to the individual patients," says Rush. Study participants who still did not achieve remission in level 2 had the option of completing up to two additional levels of treatment. Results from levels 3 and 4 of the STAR*D trial will be published later this year.
STAR*D is part of an overall NIMH effort to conduct practical clinical trials in "real world" settings that address public health issues important to those persons affected by major mental illnesses.
Prog Neuropsychopharmacol Biol Psychiatry. 2006 Nov 6;
Aripiprazole augmentation in the management of residual symptoms in clozapine-treated outpatients with chronic schizophrenia: An open-label pilot study.
Mitsonis CI, Dimopoulos NP, Mitropoulos PA, Kararizou EG, Katsa AN, Tsakiris FE, Katsanou MN.
Psychiatric Hospital of Athens, Athens University Medical School, 7, Metamorfoseos str., GR-15234 Halandri-Athens, Greece.
OBJECTIVE: The aim of this study was to investigate whether augmentation of clozapine with aripiprazole improves clinically significant residual symptoms in stabilized outpatients with chronic schizophrenia. METHODS: Twenty seven stabilized outpatients meeting criteria for chronic schizophrenia, who had residual symptoms despite clozapine treatment, were assigned to receive oral aripiprazole (15 mg/day) for a period of 16 weeks. Patients remained on clozapine (100-900 mg/day) for at least 12 months, prior to study initiation. Symptoms assessments were made with the Positive and Negative Symptom Scale (PANSS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Mini-Mental State Examination (MMSE), at baseline and at weeks 4, 8, 12, and 16. The Quality of Life Scale (QLS) was administered at baseline and at week 16. RESULTS: There was a statistically significant improvement in the mean scores for PANSS (p<0.05), PANSS negative (p<0.001), MADRS (p<0.05), MMSE (p<0.01), and QLS (p<0.05), but not for PANSS positive (p>0.05). Extrapyramidal side effects (as assessed by the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale) did not vary significantly at any point of the study. No statistically significant change was observed in prolactin levels and body weight. Results were similar for the intention-to-treat (n=27) and completer (n=23) groups. CONCLUSIONS: Aripiprazole augmentation in a group of chronic schizophrenic outpatients treated with clozapine led to a substantial improvement in clinically significant residual symptoms, such as negative-depressive symptoms, cognitive impairment and quality of life, without worsening the side effect burden.
Am J Psychiatry 163:571-573, April 2006
doi: 10.1176/appi.ajp.163.4.571
© 2006 American Psychiatric Association
EDITORIAL
Conflict of Interest
David A. Lewis, Robert Michels, Daniel S. Pine, Susan K. Schultz, Carol A. Tamminga and Robert Freedman
The accompanying editorial from Dr. Kevin Hill, written as he finished his residency, is an articulate statement of an ever-growing conflict of interest that every physician must address in recommending treatment to a patient. His problem with a drug company pen is replicated and enhanced many fold in publishing The American Journal of Psychiatry.
Surveys of physicians find that over 90% of us look to original articles in medical journals as our most preferred source of new information for help in treating patients. That responsibility requires that journals seek 1) authors whose studies yield the most useful new information, 2) reviewers who can probe the veracity of these new findings, 3) editors who can select the best articles for readers, and 4) editorial commentators who can highlight the implications for clinical practice. The object of our conflict of interest policy is to assure our readers that each author, editor, reviewer, and commentator acts only to provide the best information for clinical practice. The task is a daunting one and, for The American Journal of Psychiatry, one that involves over 2,500 submitted articles per year (of which about 250 will be selected for publication), 20 deputy and associate editors, and over 5,000 reviewers. The editors of the Journal are entrusted with the responsibility of formulating and enforcing this policy.
The management of conflict of interest begins with disclosure. Authors are required to inform the Journal about who supported their work and whether they have other financial interests that could potentially affect their article. The Journal publishes work supported by a variety of sources, usually government grants, nonprofit foundations, and pharmaceutical companies. Attention is currently focused on pharmaceutical companies because of well-publicized problems in the complete reporting of data, including the risk of suicide with antidepressant drugs. However, there are also examples of misreporting that do not involve pharmaceutical companies. In cooperation with other international medical journals, we are continually increasing our reporting of the financial interests of our authors. We have adopted the policy of requiring public reporting of the scope of clinical trials at the initiation of study, using vehicles such as www.clinicaltrials.gov, to prevent incomplete and therefore misleading reporting of a study’s results. We require that all authors have complete access to data and that all authors, including industry employees, be identified.
A second safeguard against inaccurate reporting due to conflict of interest is the review process. Editors and reviewers are experts responsible for determining whether articles are accurate reports of the studies. Their role inevitably brings up the issue of their own conflicts of interest. As Editor and Deputy Editors we have this primary responsibility, and report all our financial conflicts in the first issue of each year. We do not work with manuscripts with which we have a conflict. Similarly, reviewers and Associate Editors are asked to disclose any conflict with a manuscript they have been asked to review. The Editor is responsible for determining when such conflicts preclude participation in the editorial and review process. Manuscripts submitted by the Editor and Deputy Editors of The American Journal of Psychiatry represent a special conflict of interest. These manuscripts are handled independently by a special Associate Editor of this journal: Howard Goldman, who is Editor of Psychiatric Services.
Many journals believe that commentaries—review articles, clinical practice articles, and editorials—require special disclosure. For these articles, we ask authors to advise readers about treatment and other clinical issues. We have not set a policy that prohibits authors of commentaries from having such conflicts. Work with the pharmaceutical industry is a useful part of the activity of many clinical investigators. It enables them to interact with scientists in industry, who themselves have considerable expertise in treatment and treatment evaluation, and it enlists our best minds in the development of new therapeutics for our patients. As commentators, these individuals then bring broad experience to their role of advisers to readers. However, our readers need to know of authors’ conflicts, and we need to assure readers that articles are not influenced by conflicting interests. Therefore, we will include with commentary articles a disclosure of the authors’ relevant interests with a notation that an editor has reviewed the article to discern and exclude bias in its conclusions or its clinical recommendations.
There are two interactions in which one needs to be as free from conflicts of interest as possible: in the treatment of a patient, which is why Dr. Hill’s editorial is relevant, and in representing our field to the public. The Journal speaks directly to the public as well as to physicians about the practice of psychiatry. Therefore, the Editorial Board of the Journal and the APA Editor Search Committee required that the new Editor-in-Chief of The American Journal of Psychiatry, as its lead spokesperson, have no commercial conflicts of interest. Dr. Freedman has agreed to this requirement.
The Journal is supported primarily by our readers’ subscriptions. Our readers can be proud of having an independent journal that they support themselves as a primary source of information about their field. However, the Journal also accepts advertising as a secondary source of income. Obviously, most of the advertising is from pharmaceutical companies, which introduces another potential conflict of interest. Some of the pages of our journal are not dissimilar to Dr. Hill’s pen. How do we address this conflict of interest? First, should we accept industry advertising at all? There is no facile solution. The pharmaceutical industry is the ultimate source of most neurobiologically based psychiatric treatments, and it is the most financially successful element in the process. Therefore, it would seem self-defeating to try to ignore its presence and to eschew its support. However, the advertisements are quintessential marketing efforts, incongruously juxtaposed to our more somber articles. The cost of these advertisements is borne not by us, but by our patients.
At the present time we have a policy that restricts but does not preclude such advertising. We do not allow advertising to be facing or interleaved with articles, to prevent an advertisement for a product from appearing with an article about its use. We do not allow advertising that purports to contain educational content, such as industry-sponsored CME articles, to be part of the Journal or to be comailed to our readership. We receive repeated requests for both these features, which are highly desired by advertisers. (It should be noted, however, that article reprints—frequently purchased by industry and distributed in combination with promotional material—are a significant source of income for the Journal.)
A conflict of interest should not be mislabeled as a lack of personal integrity. There are many roles in the development and delivery of treatment to our patients. We cannot treat many of our patients without the help of the medicinal products of the pharmaceutical industry, but the industry itself cannot advocate the value of its products without the voice of independent physicians and medical journals. All of these roles involve an interaction of personal and financial interests. Conflict of interest policies do not eliminate these interactions; they simply make each person’s role apparent to everyone else. Standards are constantly changing and public perception of our independence is critical. Many industry leaders have similar beliefs. Our tolerance of overzealous marketing diminishes everyone’s credibility. Our ability to maintain our integrity as physicians and the independence of our publications is therefore critical to assure our patients of the best possible treatment now and in the future.
AMA. 2006;296:220-221.
Update on JAMA's Conflict of Interest Policy
Annette Flanagin, RN, MA; Phil B. Fontanarosa, MD, MBA; Catherine D. DeAngelis, MD, MPH
Since the mid-1980s, JAMA and other medical journals have encouraged authors to disclose conflicts of interest that they may have in the subject matter of their manuscripts.1 In 1989, JAMA began requiring authors to sign a statement declaring all potential financial conflicts of interest and began including all such disclosures in published articles.2 Since that time, the journal's conflict of interest policy has continued to evolve with the goal of improving disclosures and transparency for all involved.3-4 For example, the policy applies to all types of manuscripts, including letters and book reviews, and to all individuals involved in the review, editorial evaluation, and publication process, including peer reviewers, editorial board members, and editors. Most recently, JAMA began requiring authors to specifically indicate if they have no conflicts of interest in the subject matter of their manuscript.4 The International Committee of Medical Journal Editors (ICMJE),5 the Council of Science Editors (CSE),6 and the World Association of Medical Editors (WAME)7 have similar policies.
However, biomedical journals have a wide range of conflict of interest policies (eg, some request disclosures, some require disclosures, and some publish disclosures and some do not).8-9 Journals also define relevant conflicts of interest in different terms to include financial and nonfinancial conflicts or only financial interests, and for financial interests, may define relevance in different monetary amounts or lengths of time. Perhaps because of these different policies, some authors may not fully understand JAMA's requirements for reporting potential conflicts of interest and might not fully disclose their conflicts of interest to JAMA at the time they submit their manuscripts. For example, some authors completely disclose all relevant conflicts of interest in the submitted manuscript, whereas other authors disclose relevant interests in a cover letter or only in the authorship form. The result is an inconsistent approach whereby for some authors, the disclosure is completely transparent to all involved in the manuscript evaluation process, including peer reviewers; but for other authors, the disclosure is made public only at the time of publication. In addition, some authors continue to misunderstand what is expected and provide inaccurate or incomplete disclosures that are discovered after publication and result in a published correction or letter of explanation.10-14
To further improve the transparency of reporting of potential conflicts of interest and to encourage more accurate and complete disclosures, an important new policy is that JAMA will begin requiring all authors to disclose all potential conflicts of interest in the Acknowledgment section of the manuscript at the time of submission. This includes specific financial interests and relationships and affiliations relevant to the subject of the manuscript. Between now and the end of 2006, JAMA will permit submissions of manuscripts in which authors' conflict of interest information is not yet included in the manuscript, but with the understanding that this information will be obtained and submitted promptly—and definitely before any revisions are considered. Beginning January 2007, JAMA will require that complete disclosures of conflicts of interest from all authors, including declaration of no conflicts of interest, are included in the Acknowledgment section of the manuscript. JAMA's Web-based manuscript submission system will require the corresponding author to indicate that this information is included in the manuscript at the time of submission. Authors will continue to complete and sign an authorship responsibility form that includes statements on conflict of interest as well as funding and support.
Conflicts of interest in biomedical science continue to be under intense and increasing scrutiny. To help ensure transparency and complete reporting of this information, JAMA's policies on conflicts of interest have been updated (as noted below).15 All authors are encouraged to read these policies carefully and to follow them completely. By doing so, peer reviewers and editors can expect full disclosure of potential conflicts of interest in manuscripts submitted to JAMA, and physicians, other health care professionals, and the public can expect complete reporting of conflict of interest information in articles published in JAMA.
JAMA Conflict of Interest Policy
"A conflict of interest may exist when an author (or the author's institution or employer) has financial or personal relationships or affiliations that could influence (or bias) the author's decisions, work, or manuscript. All authors are required to disclose all potential conflicts of interest, including specific financial interests and relationships and affiliations (other than those affiliations listed in the title page of the manuscript) relevant to the subject of their manuscript. Authors should err on the side of full disclosure and should contact the editorial office if they have questions or concerns.
All such disclosures should be listed in the Acknowledgment section at the end of the manuscript. Authors without conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject of their manuscript, should include a statement of no such interests in the Acknowledgment section of the manuscript. Failure to include this information in the manuscript may delay evaluation and review of the manuscript.
Authors are expected to provide detailed information about all relevant financial interests and relationships or financial conflicts within the past 5 years and for the foreseeable future (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), particularly those present at the time the research was conducted and through publication, as well as other financial interests (such as patent applications in preparation) that represent potential future financial gain. Although many universities and other institutions have established policies and thresholds for reporting financial interests and other conflicts of interest, JAMA requires complete disclosure of all relevant financial relationships and potential financial conflicts of interest, regardless of amount or value. For example, authors of a manuscript about hypertension should report all financial relationships they have with all manufacturers of products used in the management of hypertension, not only those relationships with companies whose specific products are mentioned in the manuscript. If authors are uncertain about what constitutes a relevant financial interest or relationship, they should contact the editorial office.
For all accepted manuscripts, each author's disclosures of conflicts of interest and relevant financial interests and affiliations and declarations of no such interests will be published. Decisions about whether such information provided by authors should be published, and thereby disclosed to readers, are usually straightforward. Although editors are willing to discuss disclosure of specific conflicts of interest with authors, JAMA's policy is one of complete disclosure of all potential conflicts of interest, including specific financial interests and relationships and affiliations (other than those affiliations listed in the title page of the manuscript) relevant to the subject of their manuscript. The policy requesting disclosure of conflicts of interest applies for all manuscript submissions, including letters to the editor and book reviews. If an author's disclosure of potential conflict of interest is determined to be inaccurate or incomplete after publication, a correction will be published to rectify the original published disclosure statement.
Authors also are required to report detailed information regarding all financial and material support for the research and work, including but not limited to grant support, funding sources, and provision of equipment and supplies in the Acknowledgment section of the manuscript.
All authors must also complete and sign a statement on financial disclosures, funding, and support that is part of the Authorship Form."
AUTHOR INFORMATION
Financial Disclosures: None reported.
Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
Author Affiliations: Ms Flanagin (annette.flanagin@jama-archives.org ) is Managing Deputy Editor, Dr Fontanarosa is Executive Deputy Editor, and Dr DeAngelis is Editor in Chief, JAMA.
NEURON Volume 52, Issue 1 , 5 October 2006, Pages 139-153
Review
Neurobiology of Schizophrenia
Christopher A. Ross1, 2, 3, 4, 5, , , Russell L. Margolis1, 2, 3, 4, Sarah A.J. Reading2, 3, 6, Mikhail Pletnikov1, 2, 3 and Joseph T. Coyle7
1Division of Neurobiology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21287
2Schizophrenia Program, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21287
3Department of Psychiatry, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21287
4Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21287
5Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21287
6Division of Psychiatric Neuroimaging, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21287
7McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478
Available online 4 October 2006.
With its hallucinations, delusions, thought disorder, and cognitive deficits, schizophrenia affects the most basic human processes of perception, emotion, and judgment. Evidence increasingly suggests that schizophrenia is a subtle disorder of brain development and plasticity. Genetic studies are beginning to identify proteins of candidate genetic risk factors for schizophrenia, including dysbindin, neuregulin 1, DAOA, COMT, and DISC1, and neurobiological studies of the normal and variant forms of these genes are now well justified. We suggest that DISC1 may offer especially valuable insights. Mechanistic studies of the properties of these candidate genes and their protein products should clarify the molecular, cellular, and systems-level pathogenesis of schizophrenia. This can help redefine the schizophrenia phenotype and shed light on the relationship between schizophrenia and other major psychiatric disorders. Understanding these basic pathologic processes may yield novel targets for the development of more effective treatment
Current Psychiatry online
Vol. 5, No. 11 / November 2006
Avoiding EPS is key to realizing ‘atypical’ benefits
CATIE finding is not unique to one antipsychotic class.
Rajiv Tandon, MD
Adjunct professor of psychiatry, University of Florida, chief of psychiatry, Program Office of Mental Health, Florida Department of Children and Families, Tallahassee
Robert J. Constantine, PhD
Research associate professor, Florida Mental Health Institute, University of South Florida, Tampa
Many findings of the Clinical Antipsychotic Trials of Intervention Effectiveness in schizophrenia (CATIE) were unexpected,1,2 but one was arguably the most surprising. It was that schizophrenia patients showed similar rates of extrapyramidal symptoms (EPS), whether treated with a first-generation antipsychotic (FGA) or any of four second-generation antipsychotics (SGAs).
This finding in CATIE phase 1 runs contrary to the understanding that SGAs, compared with FGAs, provide a broader spectrum of efficacy with significantly fewer motor side effects. A substantial body of evidence and virtually all schizophrenia treatment guidelines3-5 support this prevailing view.
Did earlier schizophrenia treatment studies misinform us, or was CATIE’s comparison of FGAs and SGAs “flawed”?6,7 This article attempts to reconcile the divergent findings about antipsychotics and EPS and reveals a clinical pearl that suggests how to provide optimum antipsychotic therapy to schizophrenia patients.
CATIE was a three-phase, 18-month, randomized controlled clinical trial designed to evaluate the effectiveness of five SGAs (risperidone, olanzapine, quetiapine, ziprasidone, and clozapine) and two FGAs (perphenazine and fluphenazine) in treating schizophrenia. Findings from phases 1 and 2 have been published or presented (Table 1),2,8-9 and results from phase 3 are awaited.
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CATIE phase 1 found no difference in efficacy, safety/tolerability, or effectiveness among perphenazine, risperidone, ziprasidone, and quetiapine. Soon-to-be-published data also will show no significant difference in cognitive effects among patients receiving perphenazine or any of four SGAs (risperidone, olanzapine, quetiapine, or ziprasidone).8 Because no FGA was used in CATIE phase 2,9-11 its results added little to phase 1 observations about how “typical” and “atypical” antipsychotics compare.
‘Atypicals’ and EPS. By definition, a reduced tendency to cause EPS (such as parkinsonism, dystonia, akathisia, and akinesia) distinguishes SGAs from FGAs. In fact, SGAs were called “atypical” because they disproved the belief that EPS are an unavoidable consequence of drugs that produce an antipsychotic effect.12,13 The CATIE trial’s inability to detect a difference in EPS rates between typical and atypical antipsychotics (Table 2)2 is therefore the study’s most surprising finding.
EPS measurement | Perphenazine-treated patients | SGA-treated patients |
Increased mean | 6% | 4% to 8% |
Increased AIMS global severity score | 17% | 13% to 16% |
Increased Barnes Akathisia | 7% | 5% to 9% |
Anticholinergic added | 10% | 3% to 9% |
* Differences were not statistically significant | ||
EPS: extrapyramidal side effects | ||
SGA: second-generation antipsychotic | ||
AIMS: Abnormal Involuntary Movement Scale | ||
Most studies suggest consistent differences between FGAs and SGAs in risk of EPS and tardive dyskinesia.14-16 One explanation for CATIE’s discrepant findings may be that the use of high-dose, high-potency haloperidol as the typical comparator in pre-CATIE studies magnified differences between FGAs and SGAs.17,18
Conversely, CATIE researchers minimized this difference by studying a population of schizophrenia patients at an unusually low risk for EPS. The study design:
assigned 231 patients with a history of tardive dyskinesia to an SGA, without the opportunity to be randomly assigned to an FGA
excluded patients with first-episode schizophrenia
enrolled patients who had been treated with antipsychotics for an average of 14 years without a history of significant adverse effects from study treatments.19
Just as prior studies might have exaggerated the EPS advantage for SGAs, CATIE might have minimized the FGA-SGA difference by studying a low-risk cohort in a way that reduced the trial’s ability to detect such differences.
Interpretation. How can we reconcile the absence of a difference between FGAs and SGAs in EPS liability in CATIE with the preponderance of data suggesting otherwise? It appears that SGAs may be less likely to cause EPS than FGAs, but this difference is not evident in all populations. Furthermore, SGAs and FGAs differ in their ability to provide an adequate antipsychotic effect without EPS.
Among FGAs, low-potency agents are less likely to cause EPS or require concomitant anticholinergics than high-potency agents. Among SGAs, the gradient of EPS liability appears to be risperidone > olanzapine, aripiprazole, ziprasidone > quetiapine > clozapine (Figure). Clinically, these pharmacologic differences interact with physiologic differences in EPS vulnerability—some patients are more liable to develop EPS than others. Individuals who are more susceptible to developing EPS are more likely to benefit from antipsychotics with lower EPS liability.
CATIE found no difference among the various FGAs and SGAs with regard to overall efficacy, effects on cognition, and occurrence of tardive dyskinesia in treating chronic schizophrenia. Perhaps it was CATIE’s failure to find a difference in EPS that explains its inability to demonstrate FGA-SGA differences in cognition and other effectiveness domains.
The clinical pearlAvoiding EPS and anticholinergics appears to be the key to improving cognition, dysphoria, and negative symptoms with FGAs and SGAs. SGAs’ ability to achieve an equivalent antipsychotic effect without EPS also seems related to their lower risk of tardive dyskinesia. SGAs’ main advantage may be their greater ease of achieving an adequate antipsychotic effect without EPS or the need to add an anticholinergic to treat or prevent EPS. This comes from the broader separation between dosages at which SGAs produce their antipsychotic versus EPS effects, compared with FGAs (Figure).13 In clinical practice, then, we must achieve an adequate antipsychotic effect for our patients without EPS—whether we are using FGAs or SGAs—to obtain “atypical” benefits. The purported benefits of an “atypical” antipsychotic are not unique to a particular class of agents but relate to achieving a good antipsychotic effect without EPS—and the SGAs are better able to accomplish this than the FGAs. Careful EPS monitoring is crucial to achieving optimal antipsychotic therapy. Reduced emphasis on EPS in the past decade (in awareness of EPS and training to detect symptoms) and overlap between behavioral aspects of EPS and psychopathology need to be addressed. CATIE confirms clinical observations that: Different agents are associated with different adverse effects, which can make achieving maximum efficacy and safety/tolerability challenging. But differences among antipsychotics and heterogeneity in individual response and vulnerabilities may allow us to optimize treatment. Different agents at different dosages may provide the best outcomes for individual patients, and the optimal agent and/or dosage can vary in the same patient at different stages of the illness. The CATIE trial contributes to evidence that guides our efforts to provide optimal antipsychotic treatment of schizophrenia (Table 3). Its “surprising” findings are most useful when considered in the context of the database to which it adds.25
Related resources
DisclosuresThe authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. References
Current Psychiatry ©2006 Dowden Health Media ( Si ringrazia per la politica della libera diffusione di questo articolo) (n.d.c.) |
Current Psychiatry ©2006 Dowden Health Media Vol. 5, No. 11 / November 2006
Richard C. Shelton, MD
6 safety rules for tapering antidepressants
Side effects to discontinuing serotonin reuptake inhibitor (SRI) treatment are common and may be severe.1 Patients who are not prepared for these reactions may attribute symptoms to other causes such as a medical illness. Educate your patient about potential side effects to mitigate problems such as relapse or patient distress.
1 Warn your patient.
Alert patients to potential discontinuation reactions when prescribing any antidepressant, particularly SRIs because they seem to cause more discontinuation problems than other classes of drugs. Although reactions appear to be more common and severe with short-acting drugs such as venlafaxine and paroxetine, they can occur with longer half-life agents such as fluoxetine and sertraline.
Warn patients about discontinuation effects when starting treatment and before the planned drug taper. In particular, caution them against missing doses or stopping a drug without informing you.
2 Know the symptoms.
Common discontinuation symptoms can be grouped into six areas:
Neurosensory—vertigo, paresthesias, shock-like reactions, myalgia
Neuromotor—tremor, myoclonus, ataxia, visual changes, piloerection
Gastrointestinal—nausea, vomiting, diarrhea
Psychiatric—anxiety, depressed mood, suicidal ideation, irritability
Vasomotor—flushing, diaphoresis
Other neuropsychiatric—anorexia, insomnia, vivid dreams, asthenia, chills.2
Typical onset is rapid, and symptoms usually resolve in 2 to 3 weeks or if treatment is restarted.
3 Distinguish discontinuation reactions from relapse.
Although depressed mood and anxiety may occur during taper, these symptoms tend to be transient in most patients. Severe or persistent symptoms—including emerging suicidal ideation—may indicate a relapse.
4 Reduce medication slowly.
Tapering is recommended for all antidepressants but should be particularly slow for certain drugs—including venlafaxine, paroxetine, and clomipramine—which can cause significant discontinuation effects. For example, venlafaxine at 225 mg/d could be reduced by 75 mg/d every 1 to 2 weeks, with a final step at 37.5 mg/d for at least 1 week.
If discontinuation reactions are a problem, ultimate discontinuation may require substituting a longer-acting medication such as fluoxetine during the tapering period. For example, add fluoxetine, 10 to 20 mg/d, for 1 week, then stop both antidepressants or discontinue the first medication and continue fluoxetine for 2 to 3 weeks until the risk of reactions passes.
Clinicians often are concerned about serotonin syndrome caused by combining SRIs. Isolated cases have been reported, but the small, finite chance of serotonin syndrome is much lower than the risk of severe discontinuation reactions.
5 Titrate up and taper down.
When switching to another SRI, titrate the second drug upward while tapering off the first. Remember that changing to a drug that does not act on serotonin, such as bupropion, can protect against discontinuation effects.
6 Allow for pregnancy.
Infants born to mothers taking antidepressants can exhibit discontinuation symptoms,2 particularly with shorter-acting drugs such as paroxetine or venlafaxine. Consider tapering the antidepressant early in the patient’s third trimester, then re-institute treatment after delivery. If an antidepressant is required during pregnancy, try using one with a longer half-life such as fluoxetine.
References
Schatzberg AF, Blier P, Delgado PL, et al. Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research. J Clin Psychiatry 2006;67 (suppl 4):27–30.
Shelton RC. The nature of the discontinuation syndrome associated with antidepressant drugs. J Clin Psychiatry 2006;67(suppl 4):3–7.
Dr. Sheltonis the James G. Blakemore Research Professor and vice-chair for research, department of psychiatry, and professor of pharmacology, Vanderbilt University, Nashville, TN.
Current Psychiatry ©2006 Dowden Health Media ( Si ringrazia per la politica della libera diffusione di questo articolo) (n.d.c.)
The U.S. Food and Drug Administration (FDA) today approved Risperdal (risperidone) orally disintegrating tablets, an adult antipsychotic drug, for the symptomatic treatment of irritability in autistic children and adolescents. The approval is the first for the use of a drug to treat behaviors associated with autism in children. These behaviors are included under the general heading of irritability, and include aggression, deliberate self-injury, and temper tantrums.
"This approval should benefit many autistic children as well as their parents and other care givers," said Steven Galson, M.D., director of FDA’s Center for Drug Evaluation and Research. "Our agency strongly encourages the development of appropriate pediatric labeling for adult drugs, and Risperdal is a welcome addition to the growing number of such products that have been shown to have an appropriate risk-benefit profile when tested in children."
Risperdal has been approved since 1993 for the short-term treatment of adults with schizophrenia, and since 2003 for the short-term treatment of adults with acute manic or mixed episodes associated with extreme mood swings.
The product’s effectiveness in the symptomatic treatment of irritability associated with pediatric autistic disorders was established in two 8-week, placebo-controlled trials in 156 patients aged 5 to 16 years, 90 percent of whom were 5-12 years old. The results, which were evaluated using two assessment scales, showed that children on Risperdal achieved significantly improved scores for certain behavioral symptoms of autism compared to children on placebo. The most common side effects of the use of Risperdal included drowsiness, constipation, fatigue and weight gain.
Risperdal is marketed by Janssen, L.P. in Titusville, NJ.
FDA news
Effexor XR (venlafaxine HCl) Extended-Release Capsules
Effexor (venlafaxine HCl) Tablets
Audience: Neuropsychiatric and other healthcare professionals
[Posted 10/25/2006] Wyeth and FDA notified healthcare professionals of revisions to the OVERDOSAGE/Human Experience section of the prescribing information for Effexor (venlafaxine HCl), indicated for treatment of major depressive disorder. In postmarketing experience, there have been reports of overdose with venlafaxine, occurring predominantly in combination with alcohol and/or other drugs. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcome compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Healthcare professionals are advised to prescribe Effexor and Effexor XR in the smallest quantity of capsules consistent with good patient management to reduce the risk of overdose.
[October 17, 2006 - Letter - Wyeth]
[August, 2006 - Effexor Label - Wyeth]
[August, 2006 - Effexor XR Label - Wyeth]
Lamictal (lamotrigine)
Audience: Neurologists, obstetricians, other healthcare professionals, and patients
[Posted 09/29/2006] The FDA notified healthcare professionals and patients of new preliminary information from the North American Antiepileptic Drug Pregnancy Registry that suggests that babies exposed to Lamictal, indicated to treat seizures and bipolar disorder, during the first three months of pregnancy may have a higher chance of being born with a cleft lip or cleft palate. More research is needed to be sure about the possibility of the increased chance of cleft lip or cleft palate developing in babies of pregnant women who take Lamictal. Women who take Lamictal and are pregnant or are thinking of becoming pregnant should talk with their doctor. Patients should not start or stop using Lamictal without talking to their doctor.
[September 28, 2006
