The Expert Consensus Guideline Series
`Medication Treatment of Bipolar Disorder
`2000
`
`Gary S. Sachs, M.D.
`Director of Partners Bipolar Treatment Center, Massachusetts General Hospital
`Assistant Professor of Psychiatry, Harvard Medical School
`
`David J. Printz, M.D.
`Director of the Bipolar Disorder Research Clinic
`and Assistant Clinical Professor of Psychiatry, Columbia University
`
`David A. Kahn, M.D.
`Associate Clinical Professor of Psychiatry, Columbia University
`
`Daniel Carpenter, Ph.D.
`Vice President for Information Systems, Comprehensive NeuroScience, Inc.
`
`John P. Docherty, M.D.
`President and Chief Executive Officer, Comprehensive NeuroScience, Inc.
`
`Editing and Design. Ruth Ross, M.A., David Ross, M.A., M.C.E., Ross Editorial
`
`Acknowledgments. The authors thank Jennifer Alzona, of Expert Knowledge Systems, for managing
`the data collection, and Aysegul Yildiz, M.D., of Harvard Medical School, for work on the
`bibliography. Dr. Kahn was the project manager.
`
`Reprints. An Adobe Acrobat file of this document may be downloaded from the Internet at the Web
`site www.psychguides.com. Reprints may be obtained by sending requests with a shipping/ handling
`fee of $5.00 per copy to: AdMail, 840 Access Road, Stratford, CT 06615. For pricing on bulk orders
`of 50 copies or more, please call Expert Knowledge Systems, L.L.C., at (914) 997-4008. Single or
`bulk reprints of the patient-family guide may be obtained from the National Depressive and Manic-
`Depressive Association (NDMDA), 800-82-NDMDA (800-826-3632), or from the National
`Alliance for the Mentally Ill (NAMI), 800-950-NAMI (800-950-6264).
`
`Funding. The project was supported by unrestricted educational grants to Expert Knowledge
`Systems, LLC, and to the Health Knowledge Improvement Foundation, from Abbott Laboratories,
`Janssen Pharmaceutica, Eli Lilly and Company, Glaxo Wellcome, Ortho-McNeil Pharmaceutical,
`Pfizer, and AstraZeneca. Drs. Sachs, Printz, Kahn, and Docherty have received clinical trials
`contracts, speaking fees, or consulting fees from some or all of these companies. Although we did not
`inquire, we also believe that many of the individuals completing the survey have similar relationships.
`
`APRIL 2000 • A POSTGRADUATE MEDICINE SPECIAL REPORT •
`
`1
`
`1 of 104
`
`Alkermes, Ex. 1026
`
`

`
`Expert Consensus Guideline Series
`
`The Expert Consensus Panel for Bipolar Disorder
`The following participants in the Expert Consensus Survey were identified from several sources: recent research publications and
`funded grants, the DSM-IV advisers for mood disorders, the Task Force for the American Psychiatric Association’s Practice
`Guidelines for the Treatment of Patients with Bipolar Disorder, and those who have worked on other mood disorder guidelines. Of
`the 65 experts to whom we sent the bipolar disorder survey, 58 (89%) replied. The recommendations in the guidelines reflect the
`aggregate opinions of the experts and do not necessarily reflect the opinion of each individual on each question.
`Peter L. Forster, M.D.
`Michael R. Liebowitz, M.D.
`Michael Allen, M.D.
`University of Colorado School of Medicine
`University of California, San Francisco
`Columbia University
`
`Lori Altshuler, M.D.
`University of California, Los Angeles
`
`Claudia Baldassano, M.D.
`University of Pennsylvania
`
`Mark Frye, M.D.
`University of California, Los Angeles
`
`Alan J. Gelenberg, M.D.
`U. of Arizona Health Sciences Center
`
`Ross J. Baldessarini, M.D.
`Harvard Medical School, McLean Hospital
`
`Michael Gitlin, M.D.
`University of California, Los Angeles
`
`James C. Ballenger, M.D.
`Medical University of South Carolina
`
`Joseph F. Goldberg , M.D.
`Cornell Medical Center
`
`Husseini Manji, M.D.
`Wayne State University
`
`Lauren Marangell, M.D.
`Baylor College of Medicine
`
`Charles B. Nemeroff, M.D.
`Emory University School of Medicine
`
`Frederick Petty, M.D., Ph.D.
`VA Medical Center, Dallas
`
`Mark S. Bauer, M.D.
`Brown University, VA Medical Center, Providence
`
`Robert N. Golden, M.D.
`U. of North Carolina School of Medicine
`
`Robert M. Post, M.D.
`National Institute of Mental Health
`
`Charles L. Bowden, M.D.
`U. of Texas Health Sciences Center, San Antonio
`
`Paul J. Goodnick, M.D.
`University of Miami School of Medicine
`
`S. Craig Risch, M.D.
`Medical University of South Carolina
`
`Kathleen Brady, M.D.
`Medical University of South Carolina
`
`John H. Greist, M.D.
`Health Care Technology Systems, Madison, WI
`
`Jerrold F. Rosenbaum, M.D.
`Harvard Med. School, Mass. General Hospital
`
`Joseph R. Calabrese, M.D.
`Case Western Reserve University
`
`Laszlo Gyulai, M.D.
`University of Pennsylvania
`
`Peter Roy-Byrne, M.D.
`Harborview Medical Center, Seattle
`
`Roy Chengappa, M.D.
`Western Psychiatric Institute & Clinic
`
`Robert M.A. Hirschfeld, M.D.
`U. of Texas Medical Branch, Galveston
`
`Gary S. Sachs, M.D.
`Harvard Medical School
`
`James C.Y. Chou, M.D.
`Bellevue Hospital, New York
`
`Philip G. Janicak, M.D.
`Psychiatric Institute, U. of Illinois, Chicago
`
`David A. Solomon, M.D.
`Brown University, Rhode Island Hospital
`
`William H. Coryell, M.D.
`University of Iowa College of Medicine
`
`James W. Jefferson, M.D.
`Health Care Technology Systems, Madison, WI
`
`Andrew L. Stoll, M.D.
`Harvard Medical School, McLean Hospital
`
`Jonathan R.T. Davidson, M.D.
`Duke University Medical Center
`
`Russell Joffe, M.D.
`McMaster University
`
`Trisha Suppes, M.D., Ph.D.
`U. of Texas Southwestern Medical Center, Dallas
`
`John M. Davis, M.D.
`University of Illinois
`
`Lori Davis, M.D.
`VA Medical Center, Tuscaloosa
`
`Paul E. Keck Jr., M.D.
`University of Cincinnati College of Medicine
`
`Alan C. Swann, M.D.
`U. of Texas Health Sciences Center, Houston
`
`Gabor Keitner, M.D.
`Brown University, Rhode Island Hospital
`
`Michael E. Thase, M.D.
`University of Pittsburgh School of Medicine
`
`J. Raymond DePaulo, Jr., M.D.
`Johns Hopkins University School of Medicine
`
`Terence A. Ketter, M.D.
`Stanford University School of Medicine
`
`Peter C. Whybrow, M.D.
`UCLA, Neuropsychiatric Institute
`
`Steven L. Dubovsky, M.D.
`University of Colorado
`
`Donald F. Klein, M.D.
`Columbia University
`
`John Zajecka, M.D.
`Rush-Presbyterian-St. Luke’s Med Center
`
`David L. Dunner, M.D.
`University of Washington Medical Center
`
`K. Ranga Rama Krishnan, M.D.
`Duke University Medical Center
`
`Carlos Zarate, M.D.
`University of Massachusetts
`
`Rif S. El-Mallakh, M.D.
`University of Louisville School of Medicine
`
`Justine Lalonde, M.D.
`Massachusetts General Hospital, McLean Hospital
`
`Dwight L. Evans, M.D.
`University of Pennsylvania
`
`Robert H. Lenox, M.D.
`University of Pennsylvania
`
`2
`
`• A POSTGRADUATE MEDICINE SPECIAL REPORT • APRIL 2000
`
`2 of 104
`
`Alkermes, Ex. 1026
`
`

`
`Contents
`
`MEDICATION TREATMENT OF BIPOLAR DISORDER 2000
`
`Expert Consensus Panel..............................................................................................................................2
`Preface ......................................................................................................................................................4
`Introduction: Methods, Summary, and Commentary .................................................................................5
`Treatment Selection Algorithms ...............................................................................................................14
`
`GUIDELINES
`
`I. TREATMENT OF MANIA
`Guideline 1:
`Initial Strategy for First Manic Episode .............................................................................16
`Guideline 2: Next Step After Inadequate Response to Initial Strategy for First Manic Episode ..............18
`Guideline 3: Maintenance Treatment After a Manic Episode ................................................................21
`Guideline 4: Adequate Dose and Duration of Mood Stabilizers.............................................................24
`
`II. TREATMENT OF BIPOLAR DEPRESSION
`Guideline 5: Treatment of First Episode of Bipolar Major Depression...................................................25
`Guideline 6:
`Inadequate Response to Initial Strategy for Bipolar Depression .........................................30
`
`III. TREATMENT OF RAPID-CYCLING BIPOLAR DISORDER
`Guideline 7: Treatment of Rapid-Cycling Bipolar Disorder ..................................................................36
`
`IV. OTHER TREATMENT ISSUES
`Guideline 8:
`Selecting Medications for Bipolar Presentations That Resemble Other Disorders..............41
`Guideline 9: Use of Thyroid Hormone in Patients With Bipolar Disorder ............................................42
`Guideline 10: Managing Special Problems...............................................................................................44
`
`Bibliography
`
`.........................................................................................................................................47
`
`SURVEY RESULTS
`Expert Survey Results and Guideline References.......................................................................................50
`
`A GUIDE FOR PATIENTS AND FAMILIES ...........................................................................................97
`
`APRIL 2000 • A POSTGRADUATE MEDICINE SPECIAL REPORT •
`
`3
`
`3 of 104
`
`Alkermes, Ex. 1026
`
`

`
`Expert Consensus Guideline Series
`
`Preface
`
`McGraw-Hill Healthcare Information Programs is pleased to publish the latest revision of The
`Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder 2000. The practice
`guidelines described in this publication have employed the latest survey techniques and reflect
`only the most current clinical standards. The result is a practical reference tool not only for clini-
`cians but also for mental health educators and other healthcare professionals involved in the care
`of patients who have bipolar disorder. These guidelines, assembled under the expert direction of
`the editors (Gary Sachs, M.D., David J. Prinz, M.D., David A. Kahn, M.D., Daniel Carpenter,
`Ph.D., and John P. Docherty, M.D.), are designed to be easy to follow and use.
`
`Treating patients with bipolar disorder is never easy, and the array of pharmacologic interventions
`can be difficult to understand and deploy. These guidelines offer a “one stop” reference. They
`deal with the initial and long-term management of common scenarios as well as complicated
`treatment issues. Interventions for the specific types of bipolar disorder—mania, bipolar depres-
`sion, and rapid-cycling bipolar disorder—are outlined in detail. Initial and secondary options are
`presented for each type of disorder, along with advice regarding multiple- vs. single-drug therapy,
`side effects, and inadequate response to therapy. The section A Guide for Patients and Families
`(page 97), which includes information, resource groups, and a reference list, is exceptionally well
`done and will be practical for use by both groups. It will also serve as a helpful primer for primary
`care physicians.
`
`The printed publication will now become a valuable addition to my reference library. I hope you
`find the guidelines to be beneficial in the care of your patients.
`
`William O. Roberts, MD
`Editor-in-Chief
`McGraw-Hill Healthcare
`Information Programs
`
`4
`
`• A POSTGRADUATE MEDICINE SPECIAL REPORT • APRIL 2000
`
`4 of 104
`
`Alkermes, Ex. 1026
`
`

`
`Introduction: Methods, Summary, and Commentary
`Gary S. Sachs, M.D., David J. Printz, M.D., David A. Kahn, M.D., Daniel Carpenter, Ph.D., John P. Docherty, M.D.
`
`MEDICATION TREATMENT OF BIPOLAR DISORDER 2000
`
`ABSTRACT
`
`Objectives. New treatments for bipolar disorder have been
`reported since we first published survey-based expert
`consensus guidelines in 1996. The evidence for these
`treatments varies widely; data are especially limited regard-
`ing comparisons between treatments and how to sequence
`them. We therefore undertook a new survey of expert
`opinion in order to bridge gaps between the research
`evidence and key clinical decisions.
`
`Method. Based on a literature review, a written survey was
`prepared which asked about 1,276 options for psycho-
`pharmacologic interventions in 48 specific clinical situa-
`tions. Most options were scored using a modified version of
`the RAND Corporation 9-point scale for rating appropri-
`ateness of medical decisions. We contacted 65 national
`experts, 58 of whom (89%) completed the survey. Consen-
`sus on each option was defined as a non-random distribu-
`tion of scores by chi-square test. We assigned a categorical
`rank
`(first-line/preferred
`choice,
`second-line/alternate
`choice, third-line/usually inappropriate) to each option
`based on the confidence interval of its mean rating. Guide-
`line tables indicating preferred treatment strategies were
`then developed for key clinical situations.
`
`Results. The expert panel reached consensus on many key
`strategies, including acute and preventive treatment for
`mania (euphoric, mixed, and dysphoric subtypes), depres-
`sion, and rapid cycling, and approaches to managing the
`complications of treatment resistance and comorbidity.
`Use of a mood stabilizer is recommended in all phases
`of treatment. Divalproex (especially for mixed or dysphoric
`subtypes) and lithium are the cornerstone choices among
`this class for both acute and preventive treatment of mania.
`Regardless of which is selected first, if monotherapy fails,
`the next recommended intervention is to use these agents in
`combination. The combination can then serve as the foun-
`dation on which other medications are added, if needed.
`Carbamazepine is the leading alternative mood stabilizer
`for mania. Expert opinion regards other new anticonvul-
`sants as second-line options (e.g., if the previously men-
`tioned mood stabilizers fail or are contraindicated).
`For milder depression, a mood stabilizer, especially
`lithium, may be used as monotherapy. Divalproex and
`lamotrigine are other first-line choices. For more severe
`depression, a standard antidepressant should be combined
`with lithium or divalproex. Bupropion, selective serotonin
`reuptake inhibitors (SSRIs), and venlafaxine are preferred
`antidepressants, and should be tapered 2 to 6 months after
`remission. Divalproex monotherapy is recommended for
`
`initial treatment of either depression or mania with rapid
`cycling.
`Antipsychotics are recommended for use with the
`above regimens for mania or depression with psychosis, and
`as potential adjuncts in non-psychotic episodes. Atypical
`antipsychotics, especially olanzapine and risperidone, were
`generally preferred over conventional antipsychotics.
`Recommendations are also given concerning the use of
`electroconvulsive therapy (ECT), clozapine, thyroid hor-
`mone, stimulants, and various novel agents for patients
`with treatment-refractory illness.
`
`Conclusions. The experts reached high levels of consensus
`on key steps in treating bipolar disorder despite obvious
`gaps in high-quality data. To evaluate many of the treat-
`ment options in this survey, the experts had to extrapolate
`beyond controlled data; however, their recommendations
`are generally conservative. Experts reserve strongest
`support for initial strategies and individual medications
`for which there are high-quality research data, or for
`which there are longstanding patterns of clinical usage.
`Within the limits of expert opinion and with the under-
`standing that new research data may take precedence,
`these guidelines provide clear pathways for addressing
`common clinical questions in a manner that can be used
`to inform clinicians and educate patients regarding the
`relative merits of a variety of interventions. (Postgrad Med
`Special Report. 2000(April):1–104)
`
`WHY A REVISION?
`When we published the first Expert Consensus Guidelines
`for the Treatment of Bipolar Disorder1 in 1996 (based on
`surveys completed in 1995), we were aware that new
`research and the introduction of new treatments might
`soon require us to revise them. The 2000 Guidelines are
`our first update. We based them on a survey of 58 leading
`experts on the medication treatment of bipolar disorder.
`Because the sheer number of potentially useful medications
`has made clinical decisions ever more complex, we elected
`to focus on medications and not to review options for
`psychosocial treatment. Readers may still refer to the
`earlier edition of the Guidelines1 for information on psy-
`chosocial issues.
`The contribution of expert consensus to practice
`guideline development continues to evolve throughout
`medicine, alongside the “gold standard” of meta-analysis of
`clinical trials and other experimental data. Developers of
`guidelines throughout medicine continue to struggle with
`the problem that the number of possible combinations and
`sequences of available treatments for many diseases makes
`
`APRIL 2000 • A POSTGRADUATE MEDICINE SPECIAL REPORT •
`
`5
`
`5 of 104
`
`Alkermes, Ex. 1026
`
`

`
`Expert Consensus Guideline Series
`
`it difficult to establish practical guidelines based entirely
`on scientific data.2, 3 Our group has developed a method for
`describing expert opinion in a quantitative, reliable manner
`to help fill some of the gaps in evidence-based guidelines.
`This method has been applied to a variety of psychiatric
`disorders.1, 4–8
`
`METHOD OF DEVELOPING
`EXPERT CONSENSUS GUIDELINES
`
`Creating the Surveys
`
`We first created a skeleton algorithm based on a literature
`review. We sought to identify key decision points in the
`medication treatment of bipolar disorder as well as all the
`feasible treatment options. We highlighted important
`clinical questions that had not yet been adequately ad-
`dressed or definitely answered.9 A written questionnaire
`was then developed covering 48 specific clinical situations,
`divided into 166 subsections based on contingencies (e.g.,
`subtypes, treatment history, comorbidity) with a total of
`1,276 options for intervention. We began with questions
`concerning broad strategies, such as classes of medication,
`and then delved into tactics, such as specific medication
`selection and dosing. The survey took 2 or more hours to
`complete.
`
`The Rating Scale
`
`For 1,065 of the options in the survey, we asked raters to
`evaluate appropriateness by means of a 9-point scale
`slightly modified from a format developed by the RAND
`Corporation for ascertaining expert consensus.10 (The 211
`other options asked raters to fill in a blank, such as dosage
`or duration of treatment.) We explicitly asked the raters to
`consider both personal experience and research evidence
`(we did not provide a literature review) in making their
`ratings, but not to consider financial cost. We presented
`the rating scale to the experts with the anchors shown in
`figure 1.
`
`Figure 1. The Rating Scale
`Extremely 1 2 3 4 5 6 7 8 9 Extremely
`Inappropriate
`Appropriate
`
`9 = Extremely appropriate: this is your treatment of choice
`7–8 = Usually appropriate: a first-line treatment you would
`often use
`4–6 = Equivocal: a second-line you would sometimes use
`(e.g., patient/family preference or if first-line
`treatment is ineffective, unavailable, or unsuitable)
`2–3 = Usually inappropriate: a treatment you would rarely use
`1 = Extremely inappropriate: a treatment you would never
`use
`
`Figure 2 shows an excerpt from Survey Question 1 as
`an example of our question format.
`
`Figure 2. Sample Survey Question
`
`1. Treatment of mania: first episode, initial strategy. A physically
`healthy person in his or her 20s presents with a first manic epi-
`sode severe enough to warrant hospital admission, or a first hy-
`pomanic episode severe enough to pose a likely eventual threat
`to functioning if unchecked. Based on the dominant symptom
`pictures shown below, please rate each of the following overall
`strategies as an initial intervention, assuming the patient is
`willing to take oral medication. (Subsequent questions will ask
`you about specific medications within the broad classes.)
`
`Euphoric Mania
`
`Mood stabilizer alone
`
`Antipsychotic alone
`
`1 2 3 4 5 6 7 8 9
`
`1 2 3 4 5 6 7 8 9
`
`Mood stabilizer + antipsychotic
`
`1 2 3 4 5 6 7 8 9
`
`Benzodiazepine alone
`
`1 2 3 4 5 6 7 8 9
`
`Benzodiazepine + mood stabilizer
`
`1 2 3 4 5 6 7 8 9
`
`Benzodiazepine + mood stabilizer +
`antipsychotic
`
`1 2 3 4 5 6 7 8 9
`
`Selecting the Expert Panel
`
`We identified 65 leading American experts in bipolar disor-
`der through the following sources: authors of important
`publications in the past 5 years, recipients of research grants
`from government or industry, and members of American
`Psychiatric Association task forces for bipolar disorder
`practice guidelines and the affective disorders section of the
`Diagnostic and Statistical Manual of Mental Disorders, Fourth
`Edition (DSM-IV). We excluded individuals who had
`previously declined to complete surveys for us. We sought to
`include both new and established clinical investigators.
`
`Data Analysis for Options Scored on the Rating Scale
`
`For each option, we first defined the presence or absence of
`consensus as a distribution unlikely to occur by chance by
`performing a chi-square test (P<0.05) of the distribution of
`scores across the 3 ranges of appropriateness (1–3, 4–6, 7–
`9). Next we calculated the mean and 95% confidence
`interval (CI). A categorical rating of first-, second-, or
`third-line was designated based on the lowest category in
`which the CI fell, with boundaries of 6.5 or greater for
`first-line, and 3.5 or greater for second-line. Within first-
`line, we designated an item as “treatment of choice” if at
`least 50% of the experts rated it as 9.
`
`6
`
`• A POSTGRADUATE MEDICINE SPECIAL REPORT • APRIL 2000
`
`6 of 104
`
`Alkermes, Ex. 1026
`
`

`
`MEDICATION TREATMENT OF BIPOLAR DISORDER 2000
`
`Figure 3. Results of the Euphoric Mania Section of Survey Question 1
`
`9 5 % C O N F I D E N C E I N T E R V A L S
`Third Line
`Second Line
`First Line
`
`Tr of 1st
`2nd 3rd
`Avg(SD) Chc Line Line Line
`
`Euphoric Mania
`
`Mood stabilizer alone
`Mood stabilizer + benzodiazepine
`Mood stabilizer + antipsychotic
`Mood stabilizer + benzodiazepine + antipsychotic
`Antipsychotic alone
`Benzodiazepine alone
`
`*
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`8.0(1.4)
`7.3(1.8)
`6.4(2.2)
`5.4(2.3)
`4.0(2.0)
`2.5(1.3)
`
`57
`0
`13
`88
`36
`5
`20
`75
`15
`16
`26
`58
`6
`27
`33
`40
`2
`49
`38
`13
`0
`88
`13
`0
`% % % %
`
`Displaying the Survey Results
`
`The results of Question 1 (figure 2) are presented graphi-
`cally in figure 3. The confidence intervals (CIs) for each
`treatment option are shown as horizontal bars and the
`numerical values are given in the table on the right. (The
`display of all of the results can be found in the survey
`results section, pages 50–96.)
`
`The Ratings
`
`First-line treatments
`are those strategies that came
`out on top when the experts’ responses to the survey were
`statistically aggregated. These are options that the panel
`feels are usually appropriate as initial treatment for a given
`*
`situation. Treatment of choice,
`when it appears, is an
`especially strong first-line recommendation (having been
`rated as “9” by at least half the experts). In choosing
`between several first-line recommendations, or deciding
`whether to use a first-line treatment at all, clinicians should
`consider the overall clinical situation, including the pa-
`tient’s prior response to treatment, side effects, general
`medical problems, and patient preferences.
`
`Second-line treatments
`are reasonable choices for
`patients who cannot tolerate or do not respond to the first-
`line choices. Alternatively, a second-line choice might be
`used for initial treatment if the first-line options are
`deemed unsuitable for a particular patient (e.g., because of
`poor previous response, inconvenient dosing regimen,
`particularly annoying side effects, general medical contra-
`indication, potential drug-drug interaction, or if the
`experts don’t agree on a first-line treatment).
`For some questions, second-line ratings dominated,
`especially when the experts did not reach any consensus on
`first-line options. In such cases, to differentiate within the
`pack, we label those items whose CIs overlap with the first-
`line category as “high second-line.”
`
`Third-line treatments
`are usually inappropriate or used
`only when preferred alternatives have not been effective.
`
`No consensus.
`For each item in the survey, we used a
`chi-square test to determine whether the experts’ responses
`were randomly distributed across the 3 categories, which
`suggests a lack of consensus. These items are indicated by
`an unshaded bar in the survey results.
`
`Statistical differences between treatments. While we did
`not perform tests of significances for most treatments, the
`reader can perform an “eyeball” test by looking to see
`whether the CIs overlap (indicating no significant differ-
`ence between options by t-test). The wider the gap be-
`tween the CIs, the smaller the P value would be (i.e., the
`more significant the difference). In some questions there
`are striking and important differences within levels, which
`we occasionally point out. Often, however, the differences
`within levels are not significant from a statistical perspec-
`tive. Also, there are sometimes no statistical differences
`between choices rated at the bottom of first-line and those
`at the top of second-line.
`
`From Survey Results to Guidelines
`
`After the survey results were analyzed and ratings assigned,
`the next step was to turn these recommendations into user-
`friendly guidelines. We distinguish 2 levels, preferred op-
`tions and alternate options, that generally correspond to
`first- and higher second-line ratings. Whenever the guide-
`line gives more than 1 treatment in a rating level, we list
`them in the order of their mean scores. As an example, the
`full results of the question presented above are shown on
`page 50 and are used in Guideline 1: Initial Strategy for a
`First Manic Episode (page 16). A mood stabilizer as mono-
`therapy is the preferred initial approach for most types of
`mania, while a mood stabilizer plus an antipsychotic was
`clearly preferred for mania with psychosis. As mentioned in
`
`APRIL 2000 • A POSTGRADUATE MEDICINE SPECIAL REPORT •
`
`7
`
`7 of 104
`
`Alkermes, Ex. 1026
`
`

`
`Expert Consensus Guideline Series
`
`the legend, bold italics indicate treatment of choice rating,
`an especially strong opinion. The clinician might try these
`approaches, but move to the combinations with adjunctive
`medications if the patient could not be managed with
`monotherapy. Note that the choice of adjunct—benzodia-
`zepine or antipsychotic—differs with the subtype of mania.
`
`Summary of Results
`
`The complete set of data from the survey is presented on
`pages 50–96. The guidelines derived by the editors from
`the data are presented on pages 16–46. Graphic treatment
`algorithms summarizing the expert recommendations are
`provided on pages 14–15. We summarize the highlights
`here.
`
`Who were the panelists? Of the 65 national experts we
`contacted, 58 (89%) completed the survey. Of the 58
`completers, 35 (60%) had also completed the 1996 survey.
`The average panelist was 49 years old (standard deviation,
`9.3). Most of the panelists (80%) carry out their research
`and practice activities in non-Veterans Administration,
`non-governmental academic medical centers, typically
`spending about 25% of their time actually seeing patients;
`94% of the panel participated in clinical research on
`bipolar disorder in the past 5 years. Most of the panelists
`had seen between 20 and 100 bipolar patients in clinical
`trials in the past year and had treated additional bipolar
`patients outside clinical trials.
`
`What was the degree of consensus? Consensus was reached
`on 950 (89%) of the 1,065 options that used the rating
`scale. At least 1 first-line option was identified in 146
`(88%) of the 166 subsections. Those areas in which no
`first-line options were identified all involved complex
`comorbidities or treatment-refractory illness.
`
`What are the key recommendations? In terms of clinical
`practice, the single most important recommendation is to
`use a mood stabilizer in all phases of treatment. Divalproex
`and lithium are the cornerstone choices among this class
`for both acute-phase and preventive treatment. They
`should be tried first when monotherapy is desired, in
`combination when either has failed, and as the bedrock
`upon which other medications may be layered. The leading
`alternative mood stabilizers are carbamazepine, especially
`for mania, and the newer agent lamotrigine, especially for
`depression. The next major finding is that when an anti-
`psychotic is needed, atypicals are generally preferred over
`conventionals for initial treatment. The only presentation
`where conventionals join atypicals as a first-line option is
`mania with psychosis. A third important finding is that
`mild depression should be treated with mood stabilizer
`monotherapy initially, while severe depression should be
`treated from the start with an antidepressant plus a mood
`
`stabilizer. However, after resolution of a first episode of
`bipolar depression, antidepressants should be tapered in 2 to
`6 months, a much shorter continuation period than is
`generally advised for non-bipolar depression. A fourth
`finding is that either mania or depression with rapid cycling
`should be treated initially with a mood stabilizer alone,
`preferably divalproex for either phase. The top-rated choices
`for initial medication treatment are shown in table 1.
`
`Table 1. Top-Rated Choices for Initial Medication
`(Assumes no contraindications; adjunctive medications
`added subsequently if indicated)
`Euphoric mania or
`Lithium or divalproex
`hypomania
`Mixed or dysphoric mania Divalproex
`Mania with psychosis
`Divalproex or lithium with
`antipsychotic (atypical or
`conventional)
`Lithium
`Lithium or divalproex
`with antidepressant (plus
`atypical antipsychotic if
`delusional)
`Divalproex
`
`Milder depression
`More severe depression
`
`Mania or depression with
`recent rapid cycling
`
`Key comparisons with the last survey. Support for the use of
`divalproex has increased. Ratings for lithium and carbamaz-
`epine remain stable. Lamotrigine, which was included in this
`survey for the first time, received positive ratings for the
`treatment of bipolar depression. In an important switch,
`atypical antipsychotics are now generally rated ahead of
`conventionals. Finally, venlafaxine received significantly
`stronger ratings in this survey and joined bupropion and
`SSRIs in the group of first-line antidepressants.
`
`Key comparisons with recent literature. While panelists
`were not asked to review the literature in order to answer
`the survey, we have informally evaluated the degree to
`which their recommendations are supported by evidence.
`(It is interesting to note that a comparison of the 1996
`Guidelines with evidence-based guidelines from the Ameri-
`can Psychiatric Association and other sources revealed no
`contradictions, but differences in emphasis and in degree
`of specificity.11) The experts mostly favored treatments for
`which high-quality data, such as methodologically sound,
`placebo-controlled trials, are available. They showed
`intermediate or less support for treatments for which only
`less rigorous studies and case reports are available. Even so,
`there are many situations for which there are no well-
`controlled data, such as key drug-drug comparisons or the
`management of illness that is refractory to first-line treat-
`ments. In these situations, the panel did not display strong
`
`8
`
`• A POSTGRADUATE MEDICINE SPECIAL REPORT • APRIL 2000
`
`8 of 104
`
`Alkermes, Ex. 1026
`
`

`
`preferences—rather they supported the reasonableness of
`trying those options for which there was some evidence. For
`the treatment of refractory illness, they prefer combining or
`switching to established treatments (including ECT and
`clozapine) before experimenting with less established medi-
`cations.
`
`COMMENTARY
`What do the new survey results tell us about the state of
`optimum practice in treating bipolar disorder? In this
`section, we discuss similarities and changes since our last
`survey in 1995 and consider the relationship between
`opinion and evidence in the experts’ key decisions.
`
`Mood Stabilizers for Mania
`
`Just as in 1995, divalproex and lithium are still the highest
`rated first-line treatments for all subtypes of mania. Lith-
`ium’s numerical scores were unchanged, while scores for
`divalproex increased: scores for divalproex are now nearly
`indistinguishable from those for lithium in mania with
`euphoric mood, and divalproex is preferred as the treatment
`of choice for both mixed and dysphoric mania. These
`findings are consistent with the results of a large-scale
`prospective clinical trial comparing divalproex, lithium, and
`placebo in acute mania12 and post hoc analyses of response by
`subtype.13 Carbamazepine, as in the last survey, remains the
`most favored alternative mood stabilizer, a result that is
`consistent with it being the only other non-antipsychotic
`medication that has been shown to be effective for mania in
`well-designed studies.14 Lamotrigine received, at best, low
`second-line ratings as an initial treatment, reflecting the
`preliminary nature of the evidence for its efficacy15 and
`perhaps concern about the need for sl