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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.


New Evidence-Based Approaches in Bipolar Disorder and Schizophrenia


GOAL
To update the practicing psychiatrist on the diagnostic complexity and current treatment advances in bipolar disorder.

TARGET AUDIENCE
This activity is designed for psychiatrists. No prerequisites required.

LEARNING OBJECTIVES
The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity. At the conclusion of this activity, the participant should be able to:

  • Review the receptor profiles of the atypical antipsychotic agents in the treatment of schizophrenia and serious mental illness.
  • Recognize the similarities and differences in the various pharmacologic interventions used in treating schizophrenia.
  • Evaluate the strengths and drawbacks of the various medications used to treat schizophrenia.

ACCREDITATION STATEMENT
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 category 1 credits toward the AMA Physician's Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity.

The estimated time to complete this educational activity: 2 hours.

Release date: July 15, 2005.
Expiration date: July 15, 2007.

DISCLAIMER STATEMENT
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of The Johns Hopkins University School of Medicine name implies review of educational format, design, and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This program is supported by an educational grant from Pfizer Inc.

Full Disclosure Policy Affecting CME Activities:
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Program Director and Participating Faculty reported the following:

PROGRAM DIRECTOR

Glenn Treisman, MD, PhD
Associate Professor
Department of Psychiatry and Behavioral Sciences
The Johns Hopkins University School of Medicine
Baltimore, Maryland
Dr Treisman reports having no financial or advisory relationships with corporate organizations related to this activity.

PARTICIPATING FACULTY

Donald E. N. Addington, MBBS, MRCPsych, FRCPC
Professor of Psychiatry
Department of Psychiatry
University of Calgary
Calgary, Alberta, Canada
Dr Addington reports serving as a consultant for Lundbeck.

Peter F. Buckley, MD
Professor and Chairman
Department of Psychiatry
Medical College of Georgia
Augusta, Georgia
Dr Buckley reports receiving grants/research support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen Pharmaceutica, Novartis, Pfizer Inc, and Solvay; receiving honoraria from Abbott Laboratories, Alamo Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen Pharmaceutica, Novartis, Pfizer Inc, and Pharmastar; serving as a consultant for Abbott Laboratories, Alamo Pharmaceuticals, AstraZeneca, Bristol- Myers Squibb, Eli Lilly, Janssen Pharmaceutica, Novartis, Pfizer Inc, and Pharmastar; and serving on the speakers' bureau for Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen Pharmaceutica, Novartis, and Pfizer Inc.

Notice: The authors have indicated that this CME activity contains no mention of unlabeled/unapproved uses of drugs or devices.

Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

Understanding How Science Can Impact Clinical Care
Glenn Treisman, MD, PhD*

The introduction of chlorpromazine in 1954 ushered in a new era in psychopharmacology and the treatment of the chronically mentally ill.1 Patients with schizophrenia were able to experience alleviation of many of the symptoms that had previously been unresponsive to all interventions. The many related typical antipsychotic agents introduced over the next several decades all were similar in their presumed primary mechanism of therapeutic action, namely blockade of the dopamine D2 receptor. Although all of the typical agents shared association with tardive dyskinesia over the long term, their major differentiating features were the side-effect profiles and potency.2

Discovered in 1958, clozapine was the first atypical antipsychotic agent to be developed.3 Introduced in the United States in the early 1970s, clozapine was soon withdrawn owing to reports of potentially fatal agranulocytosis.4 Although in 1988 Kane et al demonstrated that clozapine was clinically superior compared to the typical agents in patients with treatment-resistant schizophrenia, the introduction and widespread use of this agent has been hampered by multiple side effects and the requirement of frequent blood drawing to monitor the white count.5

Since the introduction of clozapine, many new atypical agents have been introduced. Risperidone was first, followed by olanzapine, quetiapine, ziprasidone, and aripiprazole. The availability of such a broad range of treatments has resulted in greatly renewed optimism  in the treatment of schizophrenia. However, at the same time, the clinical decision-making process has become increasingly complex.

All of these agents are effective in the treatment of schizophrenia.6 They are helping to extend the range of the pharmacologic intervention and several, but not all, studies have demonstrated their improved treatment of negative symptoms and cognitive deficits.7 These symptoms have been particularly resistant to intervention with the typical agents. Yet, despite the general superiority of atypical agents in the overall treatment of the patient with schizophrenia, it has become increasingly clear that several of them carry a significant side-effect burden of their own that limits their clinical use.

This issue of Advanced Studies in Medicine will review the complex issues emerging in optimizing the treatment of patients with schizophrenia. The unique receptor profiles of the different agents8 and the ability to develop rational treatment interventions based on the data are reviewed in detail. Side effects, such as weight gain, hyperglycemia, and lipid abnormalities, most prominent with clozapine and olanzapine, may be better understood by reviewing the basic receptor actions.9 Clinical differences, such as the cognitive brightening observed with ziprasidone,10 are discussed in the context of the receptor profile, as are the effects of the unique mixed agonist/antagonist properties of aripiprazole.

The rapidly expanding pharmacologic interventions are bringing renewed hope to those afflicted with schizophrenia. However, along with the many more and diverse treatment options, the clinical complexity of the schizophrenic syndrome is making therapeutic intervention a much more difficult process. This issue is devoted to an in-depth discussion of the many challenges the clinician faces in optimizing the treatment of the chronically mentally ill.

REFERENCES
1. Lopez-Munoz F, Alamo C, Rubio G, Cuenca E. Half a century since the clinical introduction of chlorpromazine and the birth of modern psychopharmacology. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:205-208.
2. Casey DE. The relationship of pharmacology to side effects. J Clin Psychiatry. 1997;58(suppl 10):55-62.
3. Hippius HA. Historical perspective of clozapine. J Clin Psychiatry. 1999;60(suppl 12):22-23.
4. Iqbal MM, Rahman A, Husain Z, et al. Clozapine: a clinical review of adverse effects and management. Ann Clin Psychiatry. 2003;15:33-48.
5. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45:789-796.
6. Addington DE, Pantelis C, Dineen M, et al. Efficacy and tolerability of ziprasidone versus risperidone in patients with acute exacerbation of schizophrenia or schizoaffective disorder: an 8-week, double-blind, multicenter trial. J Clin Psychiatry. 2004;65:1624-1633.
7. Green MF, Marder SR, Glynn SM, et al. The neurocognitive effects of low-dose haloperidol: a two-year comparison with risperidone. Biol Psychiatry. 2002;51:972-978.
8. Stahl SM, Shayegan DK. The psychopharmacology of ziprasidone: receptor-binding properties and real-world psychiatric practice. J Clin Psychiatry. 2003;64(suppl 19):6-12.
9. Kroeze WK, Hufeisen SJ, Popadak BA, et al. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology. 2003;28:519-526.
10. Harvey PD. Ziprasidone and cognition: the evolving story.
J Clin Psychiatry. 2003;64(suppl 19):33-39.

*Associate Professor, Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Address correspondence to: Glenn Treisman, MD, PhD, Associate Professor, Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Meyer 4-119, Baltimore, MD 21205. E-mail: glenn@jhem.jhmi.edu.


Series On New Evidence-Based Approaches In Bipolar Disorder And Schizophrenia
Glenn Treisman, MD, PhD

It has been a wonderful and educational opportunity for me to help bring you this series of CME clinical reviews and discussions. I would like to thank all of the participants and contributors for their thoughtful, useful, and refreshingly clinically relevant contributions. I would also like to take this opportunity for a last brief point. This series has focused on scientific data and clinical experience. It attempts to join these in a coherent manner. The trials and studies guide clinical care, but do not define it.

Patients need the best treatment available to maximize their function. I hope that this series of articles has presented the complexity of the current decision tree in an enlightening manner rather than a daunting one. The availability of new medications has led to a proliferation of guidelines and publications to help clinicians with the difficult decisions. The data that help direct evidence-based medicine come from retrospective studies of what we have already done, and prospective trials of drugs we think may be useful based on what we have already done. It is true that there are occasional trials of new drugs that are rationally designed, but these are still the exception rather than the rule. thus it can be approved and marketed. They are Drug trials are designed to show that a drug works, designed to have as few variables as possible, and they are very expensive and thus very short. Trials are compared and occasionally head-to-head trials and out come studies are done, but even these studies often suffer from issues of patient-selection and dose-comparison issues. From the data we try to decide what to do in the real world with our patients. Drugs are often referred to as "therapeutically equivalent" if in a large trial there is no detectable difference in efficacy between 2 drugs or if trials are compared and have similar outcome. This leads to algorithms and restricted formularies. The problem is that the purpose of the trials was not to show the action of the drug in individual patients but statistical outcomes in groups over time. These trials are not designed to show that the drugs are the same in an individual. One drug is often more effective in one individual than another or it is better tolerated, thus it has better adherence and better outcome. The brief clinical trials we do to establish that a drug works are not designed to model the world of a patient where even a shade of improved function or diminished side effect can change the course of a life.

I hope the cases presented by our authors convey their focus on trying to find the best treatment for the individual patient, rather than a single fits-all approach. The current fad is saying that evidence-based medicine starts with the null hypothesis-if there has not been a study to prove that a treatment works, then it does not work. This fatalistic approach certainly conserves resources, but makes no progress. The studies we rely on were often based on the experience reported by clinicians. The demonstration of clinical efficacy usually lags behind the experience of the front-line clinician. This is not a call for irresponsible medication use and thoughtless pharmacology, but rather an understanding of what clinical trials study and demonstrate. A trial has as few variables as possible; a patient has as many variables as we can conceive.

Ultimately, the clinical goal is to provide the best improvement with the least risk and side effects. The ratio of benefit to risk should be foremost in the mind of clinicians and those who administer healthcare. In this regard, we must try to focus our efforts on making our experience and knowledge of patient care clear. We can improve the care of the mentally ill at a modest cost, with substantial results. Rehabilitation, better treatment, and hope for the future are the methods that succeed over time with difficult cases. In this regard, we must advocate for the chronically mentally ill who are unable to advocate for themselves.





Johns Hopkins Advanced Studies in Medicine (ISSN-1558-0334), is published by Galen Publishing, LLC, d/b/a ASiM, PO Box 340, Somerville, NJ 08876. (908) 253-9001. Copyright ©2012 by Galen Publishing. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, without first obtaining permission from the publisher. ASiM is a registered trademark of The Healthcare Media Group, LLC.