Martin B. Keller
`
`Improving the Course of Illness
`and Promoting Continuation of
`Treatment of Bipolar Disorder
`
`Martin B. Keller, M.D.
`
`The course and characteristics of the different types of bipolar disorder have profound implications
`for its long-term prognosis and treatment. Patients with bipolar I disorder are symptomatically ill
`nearly half the time and have a high probability of relapse. Bipolar II disorder is more chronic, more
`depressive, and associated with more neuroticism and emotional instability between episodes than
`bipolar I. Impaired psychosocial functioning and a high risk for suicide are common to all types of
`bipolar disorder. The illness can be stabilized through pharmacotherapy and by patients maintaining
`orderly patterns of life activities and using psychotherapy, psychoeducation, and mood charting. Ad-
`herence to pharmacotherapy increases the duration of remission. Physicians can help improve adher-
`ence by selecting medications with simple dosage regimens and educating patients and families about
`the disorder and what to expect from medications.
`
`(J Clin Psychiatry 2004;65[suppl 15]:10–14)
`
`T
`
`he naturalistic course and characteristics of bipolar
`disorder in its various manifestations have impor-
`tant long-term prognostic and therapeutic implications.
`The 20-year Collaborative Depression Study (CDS)1 by
`the National Institute of Mental Health has helped clarify
`distinctions among bipolar I disorder, bipolar II disorder,
`bipolar disorder not otherwise specified, and unipolar ma-
`nia and depression, and it has elucidated the natural history
`of these disorders. Nevertheless, the complexity of bipolar
`disorder and its many manifestations have led to a broad
`variance in prevalence estimates, largely because clinical
`samples have included patients with the broad spectrum of
`bipolar disorder types, including mania, hypomania, recur-
`rent and sporadic brief hypomania, depression, and cyclo-
`thymia (Table 1).
`Bipolar disorder of all types often is accompanied
`by comorbid disorders, especially anxiety disorders (panic
`attacks, agoraphobia, social phobia, and obsessive-
`compulsive syndromes) and substance abuse (tobacco de-
`pendence, alcohol abuse, illicit drug use, and overuse of
`
`From the Department of Psychiatry and Human Behavior,
`Brown University Medical School, Providence, RI.
`Based in part on a presentation at the National Summit
`Meeting of the Bipolar Care OPTIONS initiative, which was
`held September 4–6, 2003, in Washington, D.C., and supported
`by an unrestricted educational grant from Janssen Medical
`Affairs, L.L.C.
`Corresponding author and reprints: Martin B. Keller, M.D.,
`Department of Psychiatry and Human Behavior, Brown
`University Medical School, 345 Blackstone Boulevard,
`Providence, RI 02906 (e-mail: martin_keller@brown.edu).
`
`prescription drugs). A study by Kessler et al.2 concluded
`that 93% of patients with the euphoric-grandiose form of
`bipolar I disorder experience an anxiety disorder, and 71%
`have at least 1 form of substance abuse at some point in
`their lives. In addition, all types of bipolar disorder can
`have serious consequences. An estimated 7.1% to 20.3%
`of bipolar disorder patients have attempted suicide.3
`
`BIPOLAR I DISORDER
`
`Adult bipolar I disorder is highly recurrent and chronic,
`particularly in patients with a mixed/cycling or depression-
`only polarity during the intake episode.4 Greater severity
`of bipolar I disorder is associated with younger age at
`the index episode, longer duration of the index episode,
`mixed/cycling or cycling polarity, severity of depression,
`and comorbid psychosis or substance abuse, as well as so-
`cial factors such as family discord and poor socioeco-
`nomic, educational, or occupational status.5,6
`Patients with bipolar I disorder are likely to remain
`symptomatic for much of their lives, even when they are
`not experiencing an episode of mania, depression, or hypo-
`mania. In a cohort followed for a mean of 12.8 years by
`Judd and coworkers,4 patients were symptomatically ill
`nearly half the time and had an extraordinarily high prob-
`ability of relapse. Depressive symptoms occurred more
`than 3 times as often as manic symptoms in patients with
`bipolar I disorder. Depressive symptoms were present
`during 32% of the follow-up period, manic symptoms for
`9%, and cycling or mixed/cycling symptomatology for
`6%. Subsyndromal and minor depressive or dysthymic
`
`10
`
`© COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
`J Clin Psychiatry 2004;65 (suppl 15)
`
`Par Pharm., Inc.
`Exhibit 1026
`Page 001
`
`

`

`Improving the Course of Illness in Bipolar Disorder
`
`Figure 1. Cumulative Probability of Relapse in Adults With
`Bipolar I Disorder According to Polarity of the Last Episode
`(N = 172)a
`
`88 91
`
`81
`
`60 57
`
`48
`
`Mania
`Depression
`Mixed/Cycling
`
`33 36
`
`20
`
`6 mo
`
`1 y
`
`5 y
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Probability (%)
`
`aData from Keller et al.10
`
`a pure depressive episode, and 6 weeks for patients who
`experienced a pure manic episode.10
`The risk for suicide among individuals with bipolar I
`disorder is up to 30 times greater than that for the general
`population.12 The suicide risk appears to be highest early
`in the course of bipolar I disorder. Mortality associated
`with other causes—both natural and unnatural—is ap-
`proximately 2 times greater for people with the disorder
`than for the general population. In order, cardiovascular
`disease, suicide, and cancer are the 3 most frequent causes
`of death among patients with any type of bipolar disorder.
`All natural causes of death, except cancer and central ner-
`vous system diseases in men, are higher for people with
`one type of bipolar disorder.13 The significant decrements
`in psychosocial functioning that result from bipolar I disor-
`der include increased divorce rates (one study found that
`57% of the marriages of all bipolar disorder patients ended
`in divorce; divorce occurred only after, and never before,
`the first episode of mania),14 reduced functional capacity in
`virtually all domains, and a greater prevalence of alcohol
`and drug abuse.
`
`BIPOLAR II DISORDER
`
`The distinction between bipolar I disorder and bipolar II
`disorder was first hypothesized in the mid-1980s and is
`now widely accepted. Prospective studies describing the
`long-term course of bipolar II disorder are limited largely
`to those of Angst et al. in the Zurich Cohort Study15 and the
`CDS.1
`Bipolar II disorder tends to be more chronic than bipolar
`I disorder. Bipolar II is overwhelmingly more depressive
`than bipolar I disorder with far more major and minor de-
`pressive episodes. As reported by the CDS, patients with
`bipolar II disorder experience fewer and less-severe manic
`episodes, although hypomanic symptoms also can have a
`deleterious impact on the patient. Bipolar II disorder is
`marked by significantly more neuroticism, shorter inter-
`
`Table 1. Lifetime Prevalence Rates of Bipolar Disordera
`Diagnosis
`No. of Studies
`Range of Rates, %
`Bipolar I disorder
`13
`0.0–1.7
`Bipolar II disorder
`9
`0.2–3.0
`Bipolar spectrum disorders
`7
`2.6–6.5
`aData from Angst.3
`
`symptoms were more prevalent than episodes of major de-
`pression (22.9% vs. 8.9% of weeks during follow-up), and
`subsyndromal manic and hypomanic symptoms were 3
`times more frequent than symptoms at the threshold of ma-
`nia (7.0% vs. 2.3% of follow-up weeks).
`The duration of bipolar I disorder episodes is closely
`linked to their polarity. Manic episodes persisted for 6
`weeks, major depressive episodes for 12 weeks, and
`mixed/cycling episodes for 45 weeks.4,7 A 10-year prospec-
`tive follow-up8 based on observations of intraindividual
`variability in episode length among a cohort of 131 bipolar
`disorder patients found that median cycle lengths during
`the first 5 years were similar to those during the subsequent
`5 years. Episodes did not decrease systematically in length
`over time, as the researchers had expected at the initiation
`of the study. The lengths of cycles were unpredictable and
`were uncorrelated between the first 5 and second 5 years of
`the study.8
`The great majority of patients relapse after recovering
`from an episode of bipolar I disorder. Factors that predict
`recurrence of bipolar I disorder include recovery from
`a mixed/cycling episode, depression-to-mania polarity
`shifts, episode recency, a family history of mania, and non-
`adherence to prescribed medications.9 The probability of
`relapse varies with the type of episode and becomes greater
`as the length of time increases since the last episode. In a
`5-year naturalistic study, Keller et al.10 found that among
`people whose last episode was mixed/cycling, 36% re-
`lapsed after 6 months, 57% after 1 year, and 91% after 5
`years. If the last episode was depressive, 33% of patients
`relapsed after 6 months, 60% after 1 year, and 88% after 5
`years. For patients whose last episode was manic, 20% re-
`lapsed after 6 months, 48% after 1 year, and 81% after 5
`years. About 80% of all patients with bipolar I disorder will
`relapse within 5 years of a previous episode (Figure 1).
`A 10-year follow-up study found that as long as 7 years
`after recovery from the initial episode, the cumulative like-
`lihood of recurrence is 80% for all bipolar I disorder pa-
`tients and 66% for patients whose index episode was fol-
`lowed by at least 3 symptom-free years. Even with patients
`who have received sustained lithium prophylaxis, the like-
`lihood of at least 1 recurrence exceeded 70% within 5
`years of recovery.11 Among relapsed patients, those with a
`mixed/cycling episode had the lowest cumulative probabil-
`ity of recovery and needed the longest time for recovery.
`The median times to recovery were 17 weeks for patients
`who had a mixed/cycling episode, 11 weeks for those with
`
`© COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
`J Clin Psychiatry 2004;65 (suppl 15)
`
`11
`
`Par Pharm., Inc.
`Exhibit 1026
`Page 002
`
`

`

`Martin B. Keller
`
`episode intervals of euthymia, and less emotional stability
`between episodes than bipolar I disorder. Patients with
`bipolar II disorder also tended to experience less severe
`acute intake episodes in the CDS. Rapid cycling is
`common in bipolar II disorder, with cycling episodes ap-
`pearing to last more than 2 years in 20% of patients.1,15
`Rapid-cycling patients tend to be female and to exhibit
`depression, hypomania, or cycling between periods of de-
`pression and hypomania during the index episode.16
`The serious consequences of bipolar II disorder are
`similar to those of bipolar I disorder: impaired function,
`decreased productivity, increased substance abuse, psychi-
`atric and general medical comorbidity, and increased mor-
`tality, including a 10% to 15% rate of completed sui-
`cide.1,15 In addition, patients with bipolar II disorder have
`a significantly higher lifetime prevalence of anxiety dis-
`orders in general (38% of bipolar II disorder patients
`reported experiencing anxiety, compared with 25% of the
`general population), and social and simple phobias spe-
`cifically, than patients with bipolar I disorder.1
`
`AGE-SPECIFIC RESEARCH
`
`Few naturalistic/observational studies on the age-
`specific course of bipolar disorder have been undertaken.
`These include a single prospective, longitudinal study of
`childhood-onset illness,17 2 studies of adolescent-onset
`bipolar disorder,18,19 and only 2 prospective studies that
`followed adults for longer than 20 years.4,20
`Relatively few studies have been conducted on bipolar
`disorder in the elderly. One characteristic of bipolar disor-
`der among elderly people is that mania frequently may not
`manifest for many years after an initial depressive epi-
`sode. For elderly bipolar disorder patients whose initial
`episode was depressive, a mean latency period of more
`than 15 years before the first manic episode has been re-
`ported. Manic episodes also may be less severe in older
`patients. The frequency of cycles, however, appears to in-
`crease with age. Mortality rates in elderly people with bi-
`polar disorder appear to be markedly higher than in those
`who do not have bipolar disorder, although the reasons for
`the excess mortality have not been studied.21
`
`UNIPOLAR MANIA
`
`Before the CDS, most experts doubted the existence of
`unipolar mania. Available data involve only a small num-
`ber of patients who were observed for periods of up to 20
`years.22 Although unipolar mania is rare, the disorder’s di-
`agnostic validity was supported recently by Solomon and
`colleagues, who followed 27 subjects diagnosed with uni-
`polar mania on study entry. None of these patients had a
`history of major depression before entering the study.
`Seven patients had no episodes of major depression during
`the 15- to 20-year follow-up. During a prospective follow-
`
`up, 5 of those 7 patients experienced up to 8 episodes of
`hypomania lasting a total of 15 weeks.22
`
`PROGNOSIS
`
`Certain characteristics seem to be associated with a
`more favorable prognosis. Patients with the least complex
`medical and psychological make-up—those with fewer
`comorbidities and those not demonstrating mixed/cycling
`symptoms, for example—are more likely than others to
`achieve relatively good control of bipolar disorder. Reg-
`ular patterns of sleep, nutrition, and social activities are
`very beneficial, as is involvement in emotionally or finan-
`cially rewarding activities such as school or employment.
`Both sleep deprivation and substance abuse can exacer-
`bate mood disorders, and patients without those problems
`are more likely to attain better control of their disorder.
`A patient with clear insight into the nature and severity of
`his or her illness also has a better chance of maintaining
`prolonged remission. In contrast, ambivalence about the
`disease and its treatment can lead to compliance problems
`and treatment failure.12
`
`TREATMENT
`
`The recommended approach to the management of bi-
`polar disorder is a combination of medication and psycho-
`logical counseling, which should include some form of
`psychotherapy and patient education. Psychotherapy can
`include cognitive-behavioral therapy, psychoeducational
`groups, family-focused therapy (FFT), and interpersonal
`and social rhythm therapy. Central to stabilizing the illness
`is the establishment of a long-term, consistent, supportive
`environment between psychiatrist and patient that enables
`the patient to learn to accept the chronic nature of his or
`her illness and to integrate its care into daily life.12
`Family-focused therapy is a behaviorally based pro-
`gram for patients and families that provides patient educa-
`tion and training in communication and problem-solving
`skills. Family-focused therapy may be an effective adjunct
`to pharmacotherapy. The efficacy of FFT was demon-
`strated in a 9-month trial with 101 bipolar disorder pa-
`tients assigned to either FFT or 2 family education ses-
`sions and follow-up crisis management. Patients in the
`FFT group had fewer relapses, longer delays between re-
`lapses, and greater improvements in depressive, but not
`manic, symptoms. The most dramatic improvements were
`seen in families with high levels of expressed emotion.23
`Mood charting is another valuable tool that patients can
`use to record the course of their illness, the sequence of
`episodes, the patterns of cycling, and the efficacy of prior
`treatments. Through mood charting, patients can assess
`their progress with each type of treatment. Mood charting
`can provide a reliable assessment of the severity of manic
`and depressive episodes, help guide the patient and physi-
`
`12
`
`© COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
`J Clin Psychiatry 2004;65 (suppl 15)
`
`Par Pharm., Inc.
`Exhibit 1026
`Page 003
`
`

`

`cian more rapidly toward the right treatment modalities,
`and may help identify and improve outcomes in treatment-
`resistant bipolar depression. However, mood charting re-
`quires a time investment by patients and, therefore, may be
`underutilized because of time constraints.24–26
`Because bipolar disorder is a chronic illness with a high
`probability of multiple episodes, its effective control re-
`quires lifelong therapy. Unfortunately, a high proportion
`of patients with bipolar disorder frequently do not follow
`their prescribed treatment regimens. Hospital admissions
`for acute mania have been significantly associated with
`noncompliance.27 It often is difficult to determine the se-
`quence of events leading to a recurrence of bipolar dis-
`order—whether the breakthrough was a result of a patient’s
`stopping medication or whether the illness broke through
`and became severe enough so that a patient then discontin-
`ued his medication. However, 50% to 66% of patients re-
`portedly fail to comply with prescribed medications during
`the first year of treatment.15,28 According to a study by
`Schumann et al., 53.9% of patients with bipolar disorder
`discontinue their prophylactic medication at some time. Of
`those patients, 43.2% halt treatment during the first 6
`months of therapy.28 The overall prevalence of nonadher-
`ence has been estimated between 20% and 66%.27
`Many patients do not adhere to their prescribed treat-
`ment regimens because of the medications’ adverse effects;
`therefore, initial treatment decisions should consider long-
`term tolerability of therapies. If a patient is intolerant of the
`side effects of the mood stabilizer lithium, for example, the
`physician should be prepared to switch to another mood
`stabilizer, such as valproate.29 When adjusting dosage lev-
`els to manage side effects, physicians should follow pre-
`cisely the guidelines in the package insert. In lithium main-
`tenance therapy, medication dosages should be tapered
`slowly, because a sharp reduction in lithium dosage is
`linked to a high risk for symptom recurrence.30
`
`ENCOURAGING ADHERENCE
`
`Nonadherence is so prevalent with bipolar disorder pa-
`tients that clinicians should assume that their patients do
`not adhere fully to their medication regimens. A number of
`strategies are available to improve adherence. One strategy
`is, whenever possible, to select a medication with a rapid
`onset of action. Rapid onset may help reinforce adherence
`simply by causing a noticeably rapid abatement of symp-
`toms. To the extent possible, physicians should keep dos-
`age regimens simple, with a minimum number of daily
`doses. In addition, patients should be given realistic expec-
`tations about their medications’ adverse effects.
`Interventions are available to help control the side ef-
`fects that lead to nonadherence. For example, atypical anti-
`psychotics, which are used for acute mania and long-term
`maintenance, often are associated with weight gain, a ma-
`jor reason for nonadherence. A study of patients receiving
`
`Improving the Course of Illness in Bipolar Disorder
`
`atypical antipsychotics showed that they lost at least 10 lb
`by exercising, consulting with a dietician, following self-
`directed diet plans, and setting weight-loss goals; exercise
`was the most critical element in maintaining weight loss.31
`The involvement of family and friends in patient care
`can improve treatment outcomes by helping to keep the
`patient on his or her treatment regimen and improving his
`or her ability to identify symptoms of an impending re-
`lapse. In a study of family members’ involvement in pa-
`tients’ care, integrated family and individual therapy that
`included psychoeducation for patients and their families
`increased relapse-free time and reduced depressive symp-
`toms during 1 year of treatment compared with patients
`who received standard community care. Patients in both
`groups received mood-stabilizing medications.32
`Patients and their family members or other caregivers
`should be educated about the disorder and the medications
`used to treat it. The different types of psychotherapy and
`family therapy can all improve adherence by reinforcing
`patient-physician bonds.
`
`Drug name: lithium (Lithobid, Eskalith, and others).
`
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`© COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
`J Clin Psychiatry 2004;65 (suppl 15)
`
`Par Pharm., Inc.
`Exhibit 1026
`Page 005
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`