Development of TMAP Bipolar Algorithm
`
`Texas Medication Algorithm Project:
`Development and Feasibility Testing of a Treatment
`Algorithm for Patients With Bipolar Disorder
`
`Trisha Suppes, M.D., Ph.D.; Alan C. Swann, M.D.;
`Ellen B. Dennehy, Ph.D.; Ellen D. Habermacher, B.A.; Mark Mason, M.A.;
`M. Lynn Crismon, Pharm.D.; Marcia G. Toprac, Ph.D.; A. John Rush, M.D.;
`© C
`Steven P. Shon, M.D.; and Kenneth Z. Altshuler, M.D.
`
`Received Dec. 4, 2000; accepted April 3, 2001. From the Department
`of Psychiatry, University of Texas Southwestern Medical Center, Dallas
`(Drs. Suppes, Dennehy, Rush, and Altshuler and Ms. Habermacher);
`Health Science Center, University of Texas, Houston (Dr. Swann); the
`Texas Department of Mental Health and Mental Retardation (TDMHMR),
`Austin (Mr. Mason and Drs. Toprac and Shon); and the College of
`Pharmacy, University of Texas, Austin (Dr. Crismon).
`Supported in part by Mental Health Connections, a partnership
`between Dallas County Mental Health and Mental Retardation (MHMR)
`and the Department of Psychiatry of the University of Texas Southwestern
`Medical Center, which receives funding from the Texas State Legislature
`and the Dallas County Hospital District; and by grant 5 R24 MH53799-05
`(Dr. Rush) from the National Institute of Mental Health.
`Reprint requests to: Trisha Suppes, M.D., Ph.D., UT Southwestern
`Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9070
`(e-mail: Patricia.Suppes@UTSouthwestern.edu).
`
`opyright 2001 Physicians Postgraduate Press, Inc.
`
`Background: Use of treatment guidelines for
`treatment of major psychiatric illnesses has in-
`creased in recent years. The Texas Medication
`Algorithm Project (TMAP) was developed to
`study the feasibility and process of developing
`and implementing guidelines for bipolar disorder,
`major depressive disorder, and schizophrenia in
`the public mental health system of Texas. This
`article describes the consensus process used to
`develop the first set of TMAP algorithms for the
`Bipolar Disorder Module (Phase 1) and the trial
`testing the feasibility of their implementation in
`inpatient and outpatient psychiatric settings
`across Texas (Phase 2).
`Method: The feasibility trial answered core
`questions regarding implementation of treatment
`guidelines for bipolar disorder. A total of 69 pa-
`tients were treated with the original algorithms
`for bipolar disorder developed in Phase 1 of
`TMAP.
`Results: Results support that physicians ac-
`cepted the guidelines, followed recommendations
`to see patients at certain intervals, and utilized
`sequenced treatment steps differentially over the
`course of treatment. While improvements in clini-
`cal symptoms (24-item Brief Psychiatric Rating
`Scale) were observed over the course of enroll-
`ment in the trial, these conclusions are limited by
`the fact that physician volunteers were utilized for
`both treatment and ratings, and there was no con-
`trol group.
`Conclusion: Results from Phases 1 and 2
`indicate that it is possible to develop and imple-
`ment a treatment guideline for patients with a
`history of mania in public mental health clinics
`in Texas. TMAP Phase 3, a recently completed
`larger and controlled trial assessing the clinical
`and economic impact of treatment guidelines
`and patient and family education in the public
`mental health system of Texas, improves upon
`this methodology.
`(J Clin Psychiatry 2001;62:439–447)
`
`One personal copy may be printed
`
`Dfordable cost. Development of clinical practice or treat-
`
`emand is increasing for continuing improvement
`in accessible, high-quality medical care at an af-
`
`ment guidelines is one response to this demand.1 In recent
`years, as the number of treatment options has expanded,
`the field of psychiatry has adopted this trend from general
`medicine focusing on the development of treatment
`guidelines and algorithms for major psychiatric illnesses.
`Guidelines should be geared to produce (1) assistance
`for physicians to make more informed decisions, (2) maxi-
`mal symptom reduction in a majority of patients, and
`(3) maximum functional recovery.2–4 In particular, the
`effort to improve the quality of care, integration of inno-
`vation and new medications, accountability of care, and
`expected economic advantages have been powerful argu-
`ments for the use of treatment algorithms in patient man-
`agement.5–7
`As application of treatment algorithms expands, it is
`important to determine whether treatment response in
`psychiatric illnesses will, in fact, be improved through a
`systematic approach to clinical management. The utility of
`treatment algorithms or consideration of the impact of
`algorithms on aspects of care besides clinical outcome has
`yet to be demonstrated. The current article describes
`Phases 1 (guideline development) and 2 (feasibility study)
`of the Texas Medication Algorithm Project (TMAP) Bi-
`polar Disorder Module. This collaboration between aca-
`
`J Clin Psychiatry 62:6, June 2001
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`439
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`Alkermes, Ex. 1066
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`

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`Suppes et al.
`
`demic institutions and the public mental health system was
`conceived as a method to assess the feasibility and poten-
`tial benefits of implementing algorithms for treatment of
`major psychiatric illness (bipolar disorder, depression,
`schizophrenia) in public mental health clinics in Texas.7–9
`
`THE TEXAS MEDICATION
`ALGORITHM PROJECT (TMAP)
`
`© C
`
`The Texas Medication Algorithm Project began as a
`collaborative venture between the Texas Department of
`Mental Health and Mental Retardation (TDMHMR), re-
`searchers from the University of Texas Southwestern
`Medical Center and other state medical schools, and the
`College of Pharmacy at University of Texas Austin. Ulti-
`mately, community mental health centers, hospitals, and
`physicians across the state contributed to TMAP, as well
`as representatives from the National Alliance for the Men-
`tally Ill—Texas (NAMI-Texas), the Texas Depressive and
`Manic-Depressive Association (TXDMDA), the Mental
`Health Association in Texas (MHAT), and Texas Mental
`Health Consumers (TMHC). Phase I of TMAP was initi-
`ated to develop treatment algorithms for 3 major psychiat-
`ric disorders, major depressive disorder, bipolar disorder,
`and schizophrenia. Phase 2 assessed the feasibility of im-
`plementation of the developed guidelines and the re-
`sources and methods required to implement the guidelines
`in the public sector. This article describes the develop-
`ment of the original TMAP treatment algorithms for pa-
`tients with a history of mania and the feasibility test of the
`guidelines in Phase 2 of TMAP.
`
`opyright 2001 Physicians Postgraduate Press, Inc.
`
`guidelines for treatment of patients with bipolar disorder
`around this same time, but did not provide a delineated,
`specified, decision-making approach to the treatment of
`patients with bipolar disorder.15
`The Expert Consensus Guideline for treatment of
`bipolar disorder (Kahn et al., 199616; since updated in
`Sachs et al., 200012) had been completed and was in the
`process of publication. This comprehensive set of con-
`sensus guidelines was developed using a modification of
`a method developed by the Rand Corporation.17 In this
`method, a large number of national experts were asked a
`set of questions regarding specific clinical scenarios. From
`the resultant data, statistical analyses were used to iden-
`tify treatment recommendations for various clinical sce-
`narios. The first version of the Expert Consensus Guide-
`lines was organized as a “menu” of options after step 1 or
`2, rather than a delineated, ordered sequence of treatment
`stages. The Expert Consensus Guideline developers at-
`tended and presented their findings at the TMAP consen-
`sus conference, facilitating the development of the Phase
`1 algorithms.
`The goal of the Phase 1 development of a treatment
`algorithm for bipolar disorder was to integrate the avail-
`able information regarding pharmacologic treatment of
`patients with a history of mania into an understandable,
`useful format for clinicians within busy, public, commu-
`nity mental health clinics. As a first approach, the princi-
`pal investigators (PIs) (T.S. and A.C.S.) for the TMAP
`bipolar disorder module developed a proposed algorithm
`for discussion. The content and order of these proposed
`algorithms were derived from literature review, the Ex-
`pert Consensus findings, other algorithm documents, and
`clinical research experience. Research evidence was rated
`using the method widely adopted in this area, ranging
`from Level A to C evidence.2,3 Level A data are drawn
`from randomized controlled and, in most cases, blinded
`clinical trials. Level B refer to open but randomized trials
`or, in some cases, very large clinical series. Retrospective
`studies could be considered either a Level B or C, based
`on methodology. Level C consists of smaller or more scat-
`tered case reports and expert opinion or consensus. In
`general, Level A would be viewed as the strongest form of
`evidence followed by Level B and then Level C. Because
`of the new medications available and limited efficacy data
`on the combination therapies widely used with this popu-
`lation, data of all types were used to inform and further
`develop the Phase 1 algorithm for treatment of patients
`with a history of mania.
`
`One personal copy may be printed
`
`DEVELOPMENT OF THE TMAP
`BIPOLAR DISORDER GUIDELINE: PHASE 1
`
`Algorithms provide an opportunity to organize infor-
`mation from diverse sources into an easily accessible for-
`mat. As the treatment choices for bipolar disorder have
`expanded (e.g., increasing use of newer mood stabilizers,
`atypical antipsychotic agents, and combination therapies),
`a treatment algorithm provides a useful mechanism to dis-
`seminate the most current information. The assumed ben-
`efit of this tool is clearly evident in the multiple consensus
`efforts to develop treatment guidelines for this patient
`group in the absence of controlled trials informing the
`stages of treatment after monotherapy.10–13
`The conference to develop the TMAP Phase 1 treat-
`ment algorithm for care of patients with a history of mania
`(bipolar I disorder and schizoaffective disorder, bipolar
`type) was held in September 1997. At that time, the devel-
`opment of treatment algorithms in this area was limited.
`In particular, a small gathering of experts included in the
`International Psychopharmacology Algorithm Project dis-
`cussed treatment of patients with bipolar disorder.14 The
`American Psychiatric Association also published general
`
`Finalizing the Algorithm
`The second step in this process was the convening of
`a symposium in Dallas, Texas, in September 1997. At-
`tendees included multiple stakeholders in the TMAP
`project including consumers, Texas advocacy group lead-
`ers, the clinicians who would be carrying out the Phase 2
`
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`J Clin Psychiatry 62:6, June 2001
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`Development of TMAP Bipolar Algorithm
`
`sus available at the time of this symposium in 1997.
`Given the data regarding medication adherence by pa-
`tients with bipolar disorder, medication choices associ-
`ated with improved tolerability were selected (e.g., dival-
`proex sodium [Depakote] and extended-release lithium,
`such as Lithobid or Eskalith). Again, the algorithms pre-
`sented and reviewed here, developed in the fall of 1997,
`do not include the newer anticonvulsants and atypical
`antipsychotics now widely available and included in the
`TMAP Phase 3 algorithms. More updated versions of the
`TMAP algorithms for treatment of bipolar disorder can
`be found on our Web site, http://www.mhmr.state.tx.us/
`centraloffice/medical director/tmap.html.
`Specification and order of mood stabilizers. Earlier
`work within public mental health centers21 suggested that
`treatment failure in this population can often be attributed
`to inadequate dosing of mood-stabilizing medications, in-
`adequate duration of exposure, or inadequate use of com-
`bination medications. The Phase 2 algorithm for treat-
`ment of manic symptoms includes combination mood
`stabilizers in Stages 2 and 3. Based on limited data sup-
`porting response in some treatment-refractory patients,22
`the simultaneous use of carbamazepine, divalproex, and
`lithium was included as Stage 3 in the Phase 2 algorithm
`for treatment of a manic or hypomanic episode. Part of the
`discussion included education on the use of combination
`medications and, in particular, the simultaneous use of 3
`mood stabilizers as an option in the treatment algorithm
`for TMAP Phase 2.
`Inclusion of atypical antipsychotic medications. An
`additional area of discussion included the appropriate use
`and timing of atypical antipsychotics. While at first only
`clozapine was specified in the algorithm, over the course
`of the feasibility trial use of risperidone increased and was
`also allowed. Use of either clozapine or risperidone in
`conjunction with a mood-stabilizing medication for treat-
`ment of manic symptoms and/or mood lability was al-
`lowed in Stage 4 of the mania/hypomania algorithm. This
`was based in part on national clinical consensus, early
`clinical reports, and the research on efficacy of clozapine
`to treat severe affective symptoms.23–27 Adjunctive use of
`either atypical or conventional antipsychotics for psy-
`chotic symptoms was allowable at any point.
`Adjunctive medications. Another area of discussion
`centered on the use of additional sleeping medication.
`Change in sleep habits is often an early and critical symp-
`tom of imminent relapse. The decision was made not to
`recommend use of the antidepressant medication trazo-
`done because of its potential to contribute to the develop-
`ment of mania. Rather, benzodiazepines and low-dose
`divalproex were suggested.
`
`Availability and Selection of Medications
`An additional issue that often affects physician choice
`of treatment is the availability of medications. In the case
`of TMAP, the treatment guidelines were not subjected to
`limits in the choice of medications, either in brand or
`generic form. Therefore, the algorithms were not based on
`economic factors (e.g., medication acquisition costs), but
`rather on the best research evidence and clinical consen-
`
`Summary
`The goal of Phase 1 of the Texas Medication Algorithm
`Project was to develop treatment guidelines for major
`
`J Clin Psychiatry 62:6, June 2001
`
`441
`
`feasibility study in Texas, and prominent researchers who
`would serve as consultants to the project on both treat-
`ment issues and algorithm development and implementa-
`tion. Inclusion of clinicians who will be implementing an
`algorithm in the development process has been associated
`with greater support of and adherence to the final prod-
`uct.18 The principle of including academics, physicians,
`administrators, staff from public agencies, advocates, and
`consumers has been central to the success of TMAP and
`exemplifies the need to include all stakeholders in guide-
`line development.7,9,19,20
`The day included a series of individual presentations,
`including review of other guidelines and current research
`and consumer presentations and discussion of experi-
`ences. There was ample opportunity for interactive dis-
`cussion, questions, and debate by all participants. The
`generalized consensus algorithm that had been developed
`by the PIs was presented in a step-by-step manner. The
`document was discussed in detail and consensus reached.
`
`© C
`
`opyright 2001 Physicians Postgraduate Press, Inc.
`
`General Issues Regarding the Algorithms
`One of the critical discussion points was whether to
`develop separate algorithms for treatment of manic/hypo-
`manic episodes and depressive episodes. Two algorithms
`were eventually developed for TMAP Phase 2.
`The group devoted time to definitions of symptom re-
`sponse, parameters of adequate dosing, and duration of
`medication trials. Given the short duration of the Phase 2
`trial that was planned (patients treated for up to 4 months),
`a profound degree of response was not anticipated. Sug-
`gested time lines were developed, providing recommen-
`dations for clinical decisions to occur at 2 weeks, 4 weeks,
`and 6 weeks after the start of a new medication treatment.
`Certain principles to guide implementation were de-
`fined by the symposium discussions. One of the most
`important principles was that clinical judgment and pa-
`tient history superseded any specific step in the treatment
`algorithm. If a patient had a clear history of nonresponse
`or a significant side effect to a specific medication, there
`was no expectation that the patient would repeat that step.
`It was clearly communicated that the order of stages was
`based on the best available scientific data, expert consen-
`sus, and consideration of safety and tolerance issues, but
`that this order was not inflexible. Physician judgment and
`patient history and preference were expected to interact
`with the recommendations of the guideline.
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`Suppes et al.
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`Figure 1. Strategies for the Treatment of Bipolar Disorder:
`Hypomanic/Manic Episode
`
`Figure 2. Strategies for the Treatment of Bipolar Disorder:
`Major Depressive Episode
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`(cid:75)(cid:76)(cid:86)(cid:87)(cid:82)(cid:85)(cid:92)(cid:3)(cid:86)(cid:75)(cid:82)(cid:90)(cid:86)(cid:3)(cid:87)(cid:75)(cid:68)(cid:87)(cid:3)(cid:70)(cid:82)(cid:81)(cid:87)(cid:76)(cid:81)(cid:88)(cid:76)(cid:81)(cid:74)(cid:3)(cid:87)(cid:85)(cid:72)(cid:68)(cid:87)(cid:80)(cid:72)(cid:81)(cid:87)(cid:3)(cid:76)(cid:86)(cid:3)(cid:76)(cid:81)(cid:71)(cid:76)(cid:70)(cid:68)(cid:87)(cid:72)(cid:71)
`
`depressive disorder, bipolar disorder, and schizophrenia.
`The PIs of the bipolar disorder module, with feedback
`elicited in a consensus conference, developed an under-
`standable, user-friendly algorithm for use by physicians
`in busy, overburdened public mental health clinics. All
`groups present at the symposium agreed that these guide-
`lines were helpful in clinical decision making, but still
`flexible enough to be customized to individual history
`and response. Importantly, other than the International
`Psychopharmacology Algorithm Project,14 the TMAP al-
`gorithms were the first to codify and delineate a series of
`specific treatment stages taking into account efficacy,
`safety, and tolerability. The algorithms utilized in Phase 2
`of the TMAP can be viewed in Figures 1 and 2.
`
`FEASIBILITY TRIAL OF
`THE ALGORITHMS: PHASE 2
`
`The primary goal of Phase 2 was to evaluate the feasi-
`bility of integrating the treatment guidelines developed
`in Phase 1 into public mental health settings. To that end,
`the feasibility trial was designed to provide preliminary
`answers to the following questions, among others:
`(1) Would physicians accept and implement treatment
`guidelines? (2) Would use of treatment guidelines be
`
`442
`
`J Clin Psychiatry 62:6, June 2001
`
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`(cid:69)(cid:92)(cid:3)(cid:90)(cid:72)(cid:72)(cid:78)(cid:86)(cid:3)(cid:20)(cid:178)(cid:21)
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`One personal copy may be printed
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`(cid:47)(cid:76) (cid:32) (cid:47)(cid:76)(cid:87)(cid:75)(cid:76)(cid:88)(cid:80)
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`(cid:56)(cid:81)(cid:86)(cid:87)(cid:68)(cid:69)(cid:79)(cid:72)
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`(cid:11)(cid:54)(cid:87)(cid:82)(cid:83)(cid:3)(cid:38)(cid:37)(cid:61)(cid:12)
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`(cid:56)(cid:81)(cid:86)(cid:87)(cid:68)(cid:69)(cid:79)(cid:72)
`(cid:40)(cid:38)(cid:55)
`
`(cid:54)(cid:87)(cid:68)(cid:74)(cid:72)(cid:3)(cid:22)
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`(cid:54)(cid:87)(cid:68)(cid:74)(cid:72)(cid:3)(cid:23)
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`(cid:54)(cid:87)(cid:68)(cid:74)(cid:72)(cid:3)(cid:24)
`
`(cid:54)(cid:87)(cid:68)(cid:69)(cid:79)(cid:72)
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`(cid:54)(cid:55)(cid:50)(cid:51)
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`(cid:54)(cid:87)(cid:68)(cid:69)(cid:79)(cid:72)
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`(cid:54)(cid:55)(cid:50)(cid:51)
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`(cid:54)(cid:87)(cid:68)(cid:69)(cid:79)(cid:72)
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`
`opyright 2001 Physicians Postgraduate Press, Inc.
`
`4 of 9
`
`Alkermes, Ex. 1066
`
`

`

`Table 1. Basic Demographic Information of 69 Patients With
`Bipolar I Disorder or Schizoaffective Disorder, Bipolar Typea
`Outpatient
`Inpatient
`Sample (N = 44)
`Sample (N = 25)
`
`15 (34)
`29 (66)
`
`40.43
`19–65
`
`86
`14
`0
`19
`
`© C
`
`Variable
`Gender, N (%)
`Male
`Female
`Age, y
`Mean
`Range
`Ethnicity, %
`Caucasian
`African American
`Hispanic/Latino
`% Reporting a current
`alcohol/substance abuse
`problem
`Baseline symptoms
`(total 24-item BPRS score
`at first visit)
`56  15.43
`Mean  SD
`29–96
`Range
`aAbbreviation: BPRS = Brief Psychiatric Rating Scale.
`
`11 (44)
`14 (56)
`
`39.28
`18–64
`
`44
`44
`12
`48
`
`74  14.90
`49–100
`
`Development of TMAP Bipolar Algorithm
`
`clinician in their clinic. There were no data collected
`on the reliability of these ratings. The educational materi-
`als were reviewed, and parameters for providing patient
`and/or family education discussed. In addition to this ini-
`tial training session, participants were provided with a
`brief manual that covered the procedures, forms, educa-
`tional materials, and other basic questions regarding im-
`plementation.
`
`Results
`Sixty-nine patients with a diagnosis of bipolar I disor-
`der or schizoaffective disorder, bipolar type, were enrolled
`into TMAP Phase 2. Forty-four of these patients were
`treated in an outpatient setting; 25 were treated as inpa-
`tients. Demographic information about each subsample is
`included in Table 1. As this was a feasibility trial of algo-
`rithm implementation in public sector mental health cen-
`ters and hospitals, no efforts were mad