Medication Treatment of Bipolar Disorder 2000
`
`Report of the Texas Consensus Conference Panel
`on Medication Treatment of Bipolar Disorder 2000
`
`Trisha Suppes, M.D., Ph.D.; Ellen B. Dennehy, Ph.D.;
`Alan C. Swann, M.D.; Charles L. Bowden, M.D.; Joseph R. Calabrese, M.D.;
`Robert M. A. Hirschfeld, M.D.; Paul E. Keck, Jr., M.D.; Gary S. Sachs, M.D.;
`M. Lynn Crismon, Pharm.D.; Marcia G. Toprac, Ph.D.; and
`Steven P. Shon, M.D., for the Texas Consensus Conference Panel
`on Medication Treatment of Bipolar Disorder
`
`Received Aug. 24, 2001; accepted Jan. 15, 2002. From the Department
`of Psychiatry, The University of Texas Southwestern Medical Center,
`Dallas (Drs. Suppes and Dennehy); the Mental Sciences Institute, The
`University of Texas Health Science Center, Houston (Dr. Swann); the
`Department of Psychiatry, The University of Texas Health Science Center,
`San Antonio (Dr. Bowden); the Department of Psychiatry, Case Western
`Reserve University School of Medicine, Cleveland, Ohio (Dr. Calabrese);
`the Department of Psychiatry, The University of Texas Medical Branch,
`Galveston (Dr. Hirschfeld); the Department of Psychiatry, University of
`Cincinnati College of Medicine, Cincinnati, Ohio (Dr. Keck); the
`Department of Psychiatry, Harvard Medical School, Boston, Mass. (Dr.
`Sachs); the College of Pharmacy, The University of Texas at Austin, Austin
`(Dr. Crismon); and the Texas Department of Mental Health and Mental
`Retardation (TDMHMR), Austin (Drs. Toprac and Shon).
`Janssen
`Abbott Laboratories, Eli Lilly, GlaxoSmithKline,
`Pharmaceutica, and Pfizer Inc awarded unrestricted educational grants
`to support the preparation of manuscripts based on the conference
`proceedings. The conference proceedings were closed and confidential. No
`industry representatives were involved in decision making nor were aware
`of the contents resulting from the conference prior to public release of the
`information.
`Financial disclosure appears at the end of the article.
`A complete list of members of the Texas Consensus Conference Panel
`on Medication Treatment of Bipolar Disorder appears at the end of this
`article. Special thanks to the Texas Department of Mental Health and
`Mental Retardation for funding the consensus conference.
`Corresponding author and reprints: Trisha Suppes, M.D., Ph.D.,
`Associate Professor of Psychiatry, UT Southwestern Medical Center at
`Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9070 (e-mail:
`patricia.suppes@utsouthwestern.edu).
`
`One personal copy may be printed
`
`Background: The process and outcome of a
`consensus conference to develop revised algo-
`rithms for treatment of bipolar disorder to be
`implemented in the public mental health system
`of Texas are described. These medication algo-
`rithms for bipolar disorder are an update of those
`developed for the Texas Medication Algorithm
`Project, a research study that tested the clinical
`and economic impact of treatment guidelines for
`major psychiatric illnesses treated in the Texas
`public mental health system (Texas Department
`of Mental Health and Mental Retardation
`[TDMHMR]).
`Method: Academic clinicians and researchers,
`practicing clinicians in the TDMHMR system,
`administrators, advocates, and consumers parti-
`cipated in a consensus conference in August
`2000. Participants attended presentations
`reviewing new evidence in the pharmacologic
`treatment of bipolar disorder and discussed the
`needs of consumers in the TDMHMR system.
`Principles were enumerated, including balancing
`of evidence for efficacy, tolerability, and safety in
`medication choices. A set of 7 distinct algorithms
`was drafted. In the following months, a subcom-
`mittee condensed this product into 2 primary
`algorithms.
`Results: The panel agreed to 2 primary algo-
`rithms: treatment of mania/hypomania, including
`3 pathways for treatment of euphoric symptoms,
`mixed or dysphoric symptoms, and psychotic
`symptoms; and treatment of depressive symp-
`toms. General principles to guide algorithm
`implementation were discussed and drafted.
`Conclusion: The revised algorithms are
`currently being disseminated and implemented
`within the Texas public mental health system. The
`goals of the Texas initiative include increasing the
`consistency of appropriate treatment of bipolar
`disorder, encouraging systematic and optimal use
`of available pharmacotherapies, and improving
`the outcomes of patients with bipolar disorder.
`(J Clin Psychiatry 2002;63:288–299)
`
`© Copyright 2002 Physicians Postgraduate Press, Inc.
`
`Ta
`
`his article describes the process of reviewing,
`updating, and in some cases, creating treatment
`lgorithms for patients with bipolar I disorder being treated
`in the public mental health system of Texas. The revised
`algorithms will be used in the Texas Implementation of
`Medication Algorithms (TIMA) initiative, which mandates
`the use of treatment guidelines for major psychiatric
`disorders in state-funded inpatient and outpatient settings
`in Texas. Consistent with past methodologies of the Texas
`Medication Algorithm Project (TMAP), a consensus panel
`format was utilized to update previous versions of the
`algorithms.1–6
`A number of academic psychiatrists and clinical psy-
`chopharmacology specialists in the area of bipolar disorder
`were identified and invited to attend a 2-day conference in
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`Dallas, Texas, in August 2000. Additionally, administrators
`of the Texas Department of Mental Health and Mental
`Retardation (TDMHMR), physicians from community
`mental health settings, advocates, patients, and family
`members were invited to join the consensus panel. The first
`day was devoted to structured presentations and panel dis-
`cussions regarding the newest research on pharmacologic
`treatment of bipolar disorder and the goals of various in-
`terest groups regarding these algorithms. After conclusion
`of these presentations, the panel met privately through the
`evening and throughout the second day to draft the medi-
`cation algorithms.
`When possible, the consensus panel decision process
`was based on evidence rather than on expert opinion or
`clinical consensus. The consensus panel used a method
`similar to that utilized by the Agency for Healthcare
`Research and Quality (AHRQ) (formerly the Agency for
`Health Care Policy and Research [AHCPR]) in the devel-
`opment of depression guidelines. A rating system of A, B,
`or C is used to evaluate the quality of data available to
`support a recommendation: “A” representing randomized,
`blinded, and placebo-controlled trials; “B” representing
`open, controlled trials and/or large case series; and “C”
`representing early findings on smaller case reports and
`case series.7,8 Presentations on new, well-controlled treat-
`ment studies were made (including recently presented or
`in-submission studies) in order to provide the consensus
`panel with the most current evidence.
`Panel decisions were made after weighing various is-
`sues, including level of evidence in support of a treatment
`(both efficacy and effectiveness data), expert opinion, con-
`sumer input, and safety and tolerability issues. In particu-
`lar, safety and tolerability issues directly affected place-
`ment of certain treatments in the algorithm. Therefore, for
`example, the panel may have deliberated and determined
`that because of safety concerns a “level A” treatment be
`placed after a treatment with less robust evidence of treat-
`ment efficacy. Where the panel could not reach consensus,
`or there was inadequate evidence to reach a consensus, no
`opinion was rendered. Rather, where potential treatments
`had the possibility of equivalent efficacy, or there were no
`data suggesting superiority, they were included as multiple
`options within a single stage of treatment.
`The panel did not work from a restricted formulary.
`With the support of the administration of TDMHMR, they
`were asked to consider all commercially available medi-
`cations currently used in the treatment of bipolar disorder.
`The algorithms are flexible so that when equally effica-
`cious medications are available at a given stage, the prac-
`titioner is able to make decisions on the basis of individual
`patient preference, economics, or other practice priorities.
`While the goal of this conference was to develop medi-
`cation algorithms, it is not the intention of these authors to
`minimize the potential necessity and impact of other thera-
`pies, including psychotherapy, psychosocial interventions,
`
`© Copyright 2002 Physicians Postgraduate Press, Inc.
`
`and alternative and complementary treatments, in the
`treatment of bipolar disorder. The value of these and other
`interventions is recognized by this panel. Future guide-
`lines will most likely include such recommendations as
`data become available and include more comprehensive
`treatment recommendations.
`When asked to develop a set of algorithms for the treat-
`ment of patients with bipolar disorder, the consensus panel
`developed 7 distinct algorithms for different presentations
`of the disorder. This article will discuss the initial algo-
`rithms and the process by which they were condensed into
`a summary product of 2 algorithms that are feasible for
`broad-scale implementation in the public mental health
`system, with few accompanying supports or resources.
`General principles derived at the Consensus Conference
`will first be presented with discussion regarding the philo-
`sophy of guideline implementation, as well as specific
`rules that govern application of these guidelines. The treat-
`ment algorithms will then be presented.
`
`TREATMENT ALGORITHMS
`FOR BIPOLAR DISORDER
`
`The goal of the consensus panel was to integrate avail-
`able research information and clinical consensus into user-
`friendly, hierarchical decision trees of medication options
`for patients with bipolar disorder. The adoption of treat-
`ment guidelines in the TDMHMR system is not intended
`to substitute for clinician judgment or choice, but to pro-
`vide systematic guidance and structure to the array of
`potential treatment options for this patient group. The fol-
`lowing general principles are intended to disseminate the
`algorithm philosophy as well as specific implementation
`strategies endorsed by the panel.
`
`General Principles
`• The goals of treatment are (1) symptomatic remis-
`sion, (2) full return of psychosocial functioning,
`and (3) prevention of relapses and recurrences.
`• The algorithm development process was guided
`by the need to balance evidence for efficacy, toler-
`ability, and safety. These core principles are also
`expected to apply to clinical decisions for indi-
`viduals as well.
`• The treatment options recommended at the vari-
`ous points in the algorithms are based on available
`data from controlled clinical trials, open trials and
`retrospective data analyses, case reports and ex-
`pert clinical consensus, as well as expert opinion,
`consumer input, and safety and tolerability issues.
`The later stages in the algorithm involve more
`complicated regimens, while the earlier stages
`involve simpler treatments in terms of safety, tol-
`erability, ease of use, side effect profiles, etc. The
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`Medication Treatment of Bipolar Disorder 2000
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`treatment algorithms will be revised periodically
`as more controlled scientific studies (level A), the
`weight of open trials (level B), or new information
`about a given medication argues for adjustment.
`
`dose changes in a timely manner, and (3) rapidly
`identifying and correcting potential problems or ad-
`verse events associated with treatment.
`
`Clinical Management
`• All patients with bipolar disorder who achieve a sat-
`isfactory clinical response (and preferably symptom
`remission) should receive continuation phase treat-
`ment.
`• Adequate documentation should be completed
`for each algorithm stage and treatment choice
`(i.e., critical decision points). If algorithm stages are
`skipped or if treatment is different from the algo-
`rithm(s), the rationale should be adequately docu-
`mented.
`• At baseline and throughout treatment, the patient
`should be evaluated for possible psychosocial inter-
`ventions, including psychotherapy.
`• Use of the algorithms for treatment of patients with
`bipolar disorder assumes that a thorough evalua-
`tion and diagnosis has been made and that selec-
`tion of these treatments is appropriate for a given
`patient. If a patient completes trials of 2 stages of
`the algorithm without observable positive out-
`comes, it may be helpful to revisit the diagnosis
`and perform another evaluation, as well as con-
`sider mitigating factors such as substance abuse.
`• When there is a choice between brands, generic,
`or different forms (i.e., slow-release) of a recom-
`mended medication, always initiate treatment with
`the form that is most likely to be tolerated.
`
`ALGORITHMS
`
`Due to the complexity of bipolar illness, the consensus
`panel first drafted the “ideal” algorithms for treatment of
`patients with bipolar disorder, which resulted in 7 distinct
`algorithms. The 7 algorithms varied in the level of sup-
`porting data, with some relying almost exclusively on
`expert consensus. For this reason, and to increase utility
`and feasibility of large-scale implementation, a subset of
`panel participants convened a meeting to condense these 7
`algorithms into a form that could be implemented within
`the limited resources of public mental health clinics. The
`condensed product was then circulated among panel par-
`ticipants, and after several drafts, consensus was reached.
`The final product consists of an algorithm for mania/
`hypomania, which includes 3 pathways for the treatment
`of euphoric mania/hypomania, mixed or dysphoric mania/
`hypomania, and psychotic mania. A second algorithm for
`treatment of a major depressive episode is used in con-
`junction with the primary algorithm, if a patient develops
`persistent or severe depressive symptoms. Algorithms for
`treatment of rapid cycling and bipolar II disorder were
`eliminated due to the need to simplify for implementation
`
`One personal copy may be printed
`
`Choice of Treatment
`• Eligibility and point of entry into an algorithm for
`an individual patient should be determined by the
`clinician on the basis of a review of relevant gen-
`eral medical and psychiatric factors (e.g., symptom
`severity, suicidality, comorbidity), general medical
`factors (e.g., concomitant medications or illnesses,
`age), and prior treatment history.
`• If a patient responded well to a specific pharmaco-
`therapy during a previous mood episode, and it was
`well tolerated, that same treatment is recommended
`again. Similarly, a given algorithm option should
`be skipped if there is a clear history of intolerance
`and/or strong patient preference. Clinicians are
`requested to move, as much as possible, linearly
`down the algorithm. Patient history and preference
`may dictate initiating treatments from an advanced
`stage. It is also acceptable to move up the algorithm
`at a later time.
`
`Patient/Clinician Relationship
`• An adequate discussion between the clinician and
`the patient regarding available treatment options
`and specific medications (including target symp-
`toms, dosing strategies, side effect profiles, drug
`interactions, potential toxicity, and safety in over-
`dose) should occur. When medical considerations
`make several medications equivalent, clinician
`and/or patient preference may define which option
`is selected.
`• When possible, clinicians should develop a treat-
`ment plan with the patient that involves critical
`others in that person’s life. Family participation
`is encouraged not only at initial assessment, but
`also throughout the patient’s treatment, and may
`be especially helpful in monitoring the patient’s
`progress and response to medication treatments.
`• It is recommended that patients participate in their
`treatment, in part by keeping a daily mood chart or
`completing the symptom and side effect monitor-
`ing forms included as part of the TIMA bipolar
`disorder education package.
`
`Visit Frequency
`• At the beginning of entry into an algorithm, rela-
`tively frequent (e.g., every 2 weeks) patient follow-
`up appointments for further evaluation and assess-
`ment should be scheduled in order to optimize
`treatment outcomes by (1) encouraging patient
`adherence with treatment, (2) making medication
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`© Copyright 2002 Physicians Postgraduate Press, Inc.
`
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`tolerability are both evident. Measurement of serum drug
`levels is recommended when applicable to ensure adequate
`dosing is achieved prior to trying medication alternatives
`and to provide a guide to when there may be room to
`decrease the dose in a patient with good response but some
`degree of intolerance. Serum levels may also be useful
`in assisting with dosage adjustments necessary because
`of potential drug interactions. Serum levels should be
`obtained and available for applicable medications prior to
`each decision point.
`
`and the limited controlled evidence regarding best treat-
`ments for rapid cycling or bipolar II disorder. Therefore,
`the final product is intended for treatment of patients with
`a diagnosis of bipolar I disorder.
`All patients will receive treatment with the core algo-
`rithm for mania/hypomania, with the intermittent use of
`the depression treatment algorithm as needed in addition
`to the algorithm for hypomania/mania. The panel clearly
`recommended that all patients with bipolar I disorder
`receive continuing treatment with an antimanic agent from
`among those included in the core algorithm for mania/
`hypomania. These algorithms are intended for both out-
`patients and inpatients. Early stages include monotherapy
`with widely utilized medications; later stages quickly
`move to more complex medication combinations that may
`involve greater risk of side effects and require closer moni-
`toring and attention by the clinician. Patients progress
`through the stages if there is inadequate response to treat-
`ment or intolerance to medication side effects. The stages,
`along with critical research citations, consensus opinion,
`and issues regarding discussion of safety and tolerability
`for that treatment strategy, will be presented in turn. Con-
`tinuation and maintenance phase treatment issues will be
`addressed after presentation of the algorithms for acute
`phase treatment.
`Clinicians should take into consideration the following
`clinical caveats: (1) Severely ill patients should be seen
`more often (i.e., weekly) than patients who are less ill.
`Less ill but still symptomatic patients should be seen
`more often (every 2 weeks is recommended) than patients
`whose symptoms have remitted. (2) A single week of im-
`provement may not represent a stable effect. Since the
`recommendation to go to continuation phase assumes a
`stable response, patients should be evaluated for at least 2
`weeks following the first week of “response” to ensure
`stability of improvement before progressing to the con-
`tinuation phase of treatment. (3) In the continuation phase
`for mania/hypomania, patients should be seen at least
`monthly for the first 3 months, then every 2 to 3 months
`thereafter.
`The aim of treatment is symptom remission and normal-
`ization of function rather than just symptom improvement.
`Although not all patients obtain a remission, every effort
`should be made to ensure the greatest maximal benefit for
`each patient. Therefore, once a response is seen, further
`tactical (e.g., dosage adjustment or augmentation) or stra-
`tegic options (e.g., addition of medication, psychotherapy,
`or rehabilitative services) should be considered before ac-
`cepting a response that is short of remission.
`Within a stage, all medication decisions are based on
`clinician choice and patient preference. Throughout the
`algorithm, the 3 elements for making medication choices
`are efficacy or treatment response (change in symptoms),
`tolerability (side effects), and serum drug levels (when ap-
`plicable). The considerations of treatment response and
`
`© Copyright 2002 Physicians Postgraduate Press, Inc.
`
`Algorithm for Mania/Hypomania
`The algorithm for mania/hypomania (Figure 1) begins
`with the assumption that the patient has received a thorough
`evaluation and has received a diagnosis of bipolar I dis-
`order. Additionally, symptoms are severe enough to war-
`rant medication treatment. Medications that were deemed
`appropriate for treatment of hypomania and mania at the
`time of algorithm development (spring 2001) are included;
`omissions are intentional. For example, benzodiazepines
`are not included in the guideline for treatment of mania/
`hypomania because the algorithm is focused on treatments
`for the core symptoms of the disorder, although the clini-
`cian may use them for treatment of adjunctive symptoms.
`Stage 1. The options for Stage 1 include monotherapy
`with lithium, divalproex sodium, or olanzapine. These
`agents will be discussed in turn. For patients presenting
`with euphoric mania/hypomania or psychotic mania, choice
`is from any of the 3 agents. For mixed or dysphoric mania,
`the recommendation is to choose between divalproex and
`olanzapine.
`The efficacy of lithium as an antimanic agent has been
`well established. However, there are data suggesting
`that the presence of dysphoric mania predicts poorer treat-
`ment response to lithium.9–11 Therefore, lithium is not rec-
`ommended as monotherapy for that pathway. Divalproex
`is recommended as a monotherapy option for any presen-
`tation of mania/hypomania.12,13 Divalproex is specifically
`recommended, rather than valproic acid, due to its more
`favorable side effect profile and tolerability.14
`Olanzapine monotherapy for symptoms of mania/
`hypomania was added, based on placebo-controlled double-
`blind trials leading to recent U.S. Food and Drug Admin-
`istration approval of olanzapine for acute mania.15–17 A
`minority opinion of the Consensus Panel expressed concern
`at putting olanzapine as a first-line monotherapy because
`of relatively limited safety data on longer-term use of this
`drug and recent data suggesting a higher risk for develop-
`ment of diabetes.18–21
`Generally, in the case of partial response with good
`tolerance or response with residual symptoms, the recom-
`mendation will be to add a medication (move to combina-
`tion therapy, i.e., Stage 2) versus switching. If the patient
`is intolerant in Stage 1, the recommendation will be to try
`an alternative mood stabilizer within Stage 1.
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`Medication Treatment of Bipolar Disorder 2000
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`Stage 2. Use of combination therapy essentially has
`become standard care in the treatment of the majority of
`patients with bipolar disorder,22–24 as recognized through
`clinical consensus and expert opinion versus controlled
`data. Similar to other recently published algorithms for
`treatment of bipolar disorder,25–27 Stage 2 treatment includes
`combination treatment with 2 agents. Clinicians may choose
`from the following: lithium, divalproex, oxcarbazepine,
`olanzapine, or risperidone. Therefore, the combination is
`either lithium or an anticonvulsant plus an anticonvulsant,
`or lithium or an anticonvulsant plus an atypical anti-
`psychotic [(Li or AC) + AC, or (Li or AC) + AAP]. Oxcar-
`bazepine and risperidone are added as options here. While
`there are no double-blind, placebo-controlled trials support-
`ing risperidone monotherapy, there is 1 small double-blind,
`randomized, single-site trial,28 an add-on trial,29 and open
`reports that support its use in combination.30–33 Oxcarbaze-
`pine is structurally similar to carbamazepine, but does not
`produce the epoxide metabolite, which is thought to be as-
`sociated with much of the toxicity and intolerance associ-
`ated with carbamazepine. Oxcarbazepine has been shown
`to have comparable efficacy in studies of epilepsy and pre-
`liminary work in bipolar patients. It is associated with in-
`creased tolerability and fewer drug interactions and does not
`require serum level monitoring.34–44 Therefore, consistent
`with the general principle to use forms of medications as-
`sociated with greatest tolerability, oxcarbazepine is recom-
`mended. While carbamazepine is not included as a mono-
`therapy option, it is recommended in combination with
`other antimanic drugs.45–50 A minority opinion within the
`panel was that further efficacy data in bipolar patients were
`needed before including oxcarbazepine in the algorithm.
`Stage 3. In Stage 3, clinicians are asked to attempt
`another combination of medications, drawing from the
`same group described in Stage 2. Preferably, they would
`keep one agent from the previous combination and change
`to a different second agent. Again, the combination can be
`either (Li or AC) + AC, or (Li or AC) + AAP.
`Stage 4. This stage also includes combination therapy,
`but at this point, the clinician is prompted directly to use
`an atypical antipsychotic agent in combination with lithium,
`divalproex, or oxcarbazepine (i.e., [Li or AC] + AAP). For
`patients with psychotic mania, the recommendation is to
`progress immediately to this combination if Stage 1 mono-
`therapy with lithium, divalproex, or olanzapine is ineffec-
`tive or only partially effective. Quetiapine and ziprasidone
`are added as additional choices here. Quetiapine has a num-
`ber of open and double-blind trials supporting its utility
`in combination with other medications for bipolar disor-
`der.51–56 Ziprasidone has one completed double-blind,
`placebo-controlled, multicenter trial of monotherapy in
`210 inpatients with mania, which supports its antimanic
`properties.57
`Stage 5. Stage 5 includes “triple therapy,” with lithium,
`an anticonvulsant (choose from divalproex or oxcarbaze-
`
`© Copyright 2002 Physicians Postgraduate Press, Inc.
`
` Li = Lithium
` AC = Anticonvulsant
` DVP = Divalproex
` LTG = Lamotrigine
` OXC = Oxcarbazepine
` TPM = Topiramate
` AAP = Atypical Antipsychotic
` OLZ = Olanzapine
` RIS = Risperidone
` QTP = Quetiapine
` ZIP = Xiprasidone
` ECT = Electronconvulsive Therapy
`CONT = continue
`
`This material is in the
`public domain and
`can be reproduced
`without permission,
`but with appropriate
`citation.
`
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`Figure 1. Algorithm for Treatment of Mania/Hypomania in
`Patients With Bipolar I Disorder
` Mixed or
`Dysphoric
`Mania/
`Hypomania
`
`Euphoric
`Mania/
`Hypomania
`Li or DVP
` or OLZ
`
`Stage 1
`
`Monotherapy
`
`DVP or OLZ
`
`Response
`
`CONT
`
`Psychotic
`Mania
`Li or DVP
` or OLZ
`
`Response
`
`CONT
`Partial Response
`or Nonresponse
`
`Partial Response
`or Nonresponse
`[(Li or AC) + AC] or
`[(Li or AC) + AAP]
`Choose From:
`Li, DVP, OXC, OLZ, RIS
`
`Two-Drug
`Combination
`
`Response
`
`CONT
`
`Stage 2
`
`Stage 3
`
`Partial Response
`or Nonresponse
`[(Li or AC) + AC] or
`[(Li or AC) + AAP]
`Choose From:
`Li, DVP, OXC, OLZ, RIS
`
`Two-Drug
`Combination
`
`Response
`
`Partial Response
`or Nonresponse
`
`CONT
`
`Stage 4
`
`Two-Drug
`Combination
`
`Stage 5
`
`Triple
`Combination
`
`Stage 6
`
`Stage 7
`
`(Li or AC) + AAP
`Choose From: Li, DVP, OXC,
`OLZ, RIS, QTP, ZIP
`
`Response
`
`CONT
`
`Partial Response
`or Nonresponse
`Li + AC + AAP
`Choose AC From DVP or OXC
`Choose AAP From OLZ, RIS, QTP, ZIP
`
`Response
`
`CONT
`
`Partial Response
`or Nonresponse
`ECT
`or
`Add Clozapine
`
`Response
`
`CONT
`
`Partial Response
`or Nonresponse
`Other
`(TPM, AAP + AAP,
`Conventional Antipsychotics, LTG)
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`Figure 2. Algorithm for the Treatment of Depression in
`Bipolar I Disorder (to be used in conjunction with the
`primary treatment algorithm for mania/hypomania)
`
`Stage 1
`
`Initiate or Optimize ((cid:66)(cid:63)Dose)
`Mood-Stabilizing Medications
`
`Partial Response
`or Nonresponse
`
`Stage 2
`
`AD1 or LTG
`
`Response
`
`CONT
`
`with clinical recommendations to attempt treatment with
`other atypical antipsychotic medications before initiating
`clozapine treatment due to potential tolerability difficul-
`ties and the medical monitoring required.
`Stage 7. This stage includes other options that may be
`used as adjuncts to partially effective medication combi-
`nations and medications with more limited data. It includes
`topiramate,64–69 a combination of medications that includes
`2 atypical antipsychotic medications, conventional anti-
`psychotics, and lamotrigine.70–74
`
`© Copyright 2002 Physicians Postgraduate Press, Inc.
`
`This material is in the
`public domain and
`can be reproduced
`without permission,
`but with appropriate
`citation.
`
`AAP = Atypical Antipsychotic
` AD = Antidepressant
`ECT = Electronconvulsive Therapy
`MAOI = Monoamine Oxidase Inhibitor
` AD1 = Bupropion Sustained Release or
`Selective Serotonin Reuptake Inhibitor
` AD2 = Venlafaxine or Nefazodone
` LTG = Lamotrigine
`CONT = continued
`
`pine), and an atypical antipsychotic medication (choose
`from olanzapine, risperidone, quetiapine, or ziprasidone).
`Stage 6. Electroconvulsive therapy (ECT) is an effec-
`tive treatment for acute mania,58,59 but safety, tolerability,
`and patient acceptance issues led to its placement further
`down in the algorithm at Stage 6. Many manic patients
`will experience a relatively rapid response to ECT. Rec-
`ommended frequency is 3 treatments per week, and ECT
`should be terminated when patients are in full remission
`or fail to sustain response over 3 to 6 treatments. At least 6
`to 10 ECT treatments should be attempted before declar-
`ing a patient resistant to treatment.
`Alternatively, clozapine could be added to other medi-
`cations as a treatment option here.60–63 This is consistent
`
`
`
`294293
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`J Clin Psychiatry 63:4, April 2002
`
`Strategies to Treat Depression in Bipolar Disorder
`The majority of the algorithm of strategies to treat
`depression in bipolar I disorder (Figure 2) is based on
`expert consensus, given the limited evidence for treatment
`of depression in patients with bipolar disorder. Several
`treatments that do have evidence supporting their effective-
`ness are listed at advanced stages due to issues regarding
`safety and tolerability (monoamine oxidase inhibitor
`[MAOI] medications, electroconvulsive therapy [ECT]).
`Within some stages (e.g., Stage 3), several options are pro-
`vided because the evidence does not support a more spe-
`cific order of those treatment strategies. It is assumed that
`this algorithm will be utilized in conjunction with the pri-
`mary treatment algorithm for mania/hypomania. If a patient
`reports symptoms of depression significant enough to war-
`rant intervention, the clinician is directed to utilize this
`algorithm as a concomitant treatment strategy in addition
`to any stage of treatment within the mania/hypomania
`algorithm. As with any algorithm, if insufficient response
`in depressive symptoms is achieved, the clinician should
`continue through the algorithm until satisfactory symptom
`reduction is achieved.
`It is important to carefully consider the addition of
`an antidepressant to the medication regimen of patients
`with bipolar disorder. The decision is simplified when the
`patient has a distinct major depressive episode, without
`mood lability or hypomania, and the degree of suffering
`justifies initiating an antidepressant. However, many
`patients will have significant depressive symptoms, but
`also periods of dysphoric hypomania, mood lability, irri-
`tability, and other more complicated states.75–79 The balance
`of optimizing mood stabilizers, possibly adding lithium, or
`adding an antidepressant must be done on a case-by-case
`basis. Regardless, the consensus panel maintains that all
`bipolar depressed patients should have mood-stabilizer
`treatment optimized.80
`The algorithm to treat depression in bipolar disorder
`assumes antidepressants will be used only in conjunction
`with a mood-stabilizing medication, because of the risk of
`inducing manic symptoms.81–83 If a patient develops hypo-
`manic, manic, or mixed symptoms after initiation of an
`antidepressant agent, the agent should be stopped and those
`symptoms treated. It may be necessary to adjust the mood
`stabilizer during treatment (i.e., increase dose with devel-
`
`Stage 3
`
`Stage 4
`
`Stage 5
`
`Stage 6
`
`CONT
`
`CONT
`
`CONT
`
`CONT
`
`Response
`
`Partial Response
`or Nonresponse
`Add Lithium or
`Switch to Alternate AD
`(AD1, LTG, or AD2)
`or
`Add Additonal AD
`(AD1, LTG, or AD2)
`
`Response
`
`Partial Response
`or Nonresponse
`Combination of 2 Antidepressants
`(Choose From AD1, LTG, or AD2)
`
`Response
`
`Partial Response
`or Nonresponse
`Switch AD to an MAOI or
`Add AAP Medication
`
`Response
`
`Partial Response
`or Nonresponse
`Use Alternative Not Used at Stage 5
`or ECT or Other
`(Inositol, Dopamine Agonists, Stimulants,
`Thyroid, Conventional Antipsychotics,
`Tricyclic Antidepressnats, Omega 3
`Fatty Acids, Acupuncture, Hormones)
`
`One personal copy may be printed
`
`6 of 12
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`Alkermes, Ex. 1067
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`Medication Treatment of Bipolar Disorder 2000
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