A method for classifying the course of bipolar I disorder

BEHAV1ORTHERAPY30, 355-372, 1999

A Method for Classifying the Course of Bipolar I Disorder APARNA S. KALBAG DAVID J. MIKLOW~TZ JEFFREY A . RICHARDS University of Colorado at Boulder Our objective was to determine whether the long-term course of bipolar disorder could be classified into distinct categories based on specifiable course characteristics. We used retrospective data on the severity, duration, and polarity of episodes, and on interepisode functioning, to describe the life trajectories of 56 bipolar patients. Using pictorial representations from a Life Chart software program, we identified seven distinct course types. Interrater reliability for classification of patients into these course types was high. Post-hoc analyses revealed significant relationships between the broader dimensions underlying the proposed course types (i.e., primarily manic vs. mixed symptom profiles) and traditional course of illness variables (e.g., the number of lifetime hospitalizations). This course classification method may provide a means for documenting progress in behavior therapy outcome studies.

Bipolar disorder manifests itself in different forms. The illness can vary over time in severity, cyclicity, and polarity of its core symptoms, and different patients can show quite different cycling patterns. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association [APA], 1994) has criteria for distinguishing different forms of the disorder, at least as pertaining to a patient's most recent episode. For example, patients presenting with bipolar I disorder can now be distinguished from those with bipolar II disorder by the occurrence of full-blown manic or mixed episodes rather than hypomanic episodes. Further, when the patient presents in a clinical remission and there is evidence of prior mood disorder episodes, DSM-IV offers criteria sets for more thoroughly describing the most recent episode (i.e., severity, polarity). However, these diagnostic criteria sets This research was supported by grants MH43931, MH42556, and MH55101 from the National Institute of Mental Health (NIMH); an NIMH research supplement for underrepresented minorities; a grant from the John D. and Catharine T. MacArthur Network on the Psychobiology of Depression; and a Faculty Fellowship from the University of Colorado's Council on Research and Creative Work. Address correspondence to Dr. David J. Miklowitz, Department of Psychology, University of Colorado at Boulder, Campus Box 345, Boulder, CO 80309-0345. 355 005-7894/99/0355-037251.00/0 Copyright 1999by Associationfor Advancementof BehaviorTherapy All rightsfor reproductionin any form reserved.

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are largely cross-sectional in nature, and do not capture the variability in the course of the disorder over time. Delineating reliable, easily recognizable illness subtypes over longitudinal periods of follow-up would help in assessing whether bipolar patients are responsive to various forms of behavioral, psychoeducational, or pharmacological treatments. First, knowing that a patient has followed a particular course of illness prior to the initiation of a behavioral treatment would help clinicians or researchers evaluate whether the program has a long-term impact. Second, bipolar patients, and sometimes their family members, are reluctant to accept that the illness is likely to be recurrent and requires lifestyle adjustments (Miklowitz & Goldstein, 1997). Through reviewing past subsyndromal and episodic symptom patterns, as captured in an operationalized classification system, patients and family members may develop a greater awareness of the context in which new episodes occur. Clinicians may then be able to train patients to recognize their own cycling patterns and prodromal symptoms.

Prior Classification Systems Longitudinal course descriptors (e.g., severity of episodes) and the level of interepisode recovery have traditionally been used in describing the life trajectories of schizophrenic patients (Bleuler, 1978; Ciompi, 1980; Harding, 1989). Course descriptors aid in understanding the context within which an episode occurs. Goodwin and Jamison (1990) propose that patients with bipolar disorder differ from each other on eight variables that characterize their courses of illness: severity of depressive states, severity of manic states, severity of mixed states, polarity of episodes (i.e., manic vs. mixed vs. depressed), duration of episodes, cyclicity, instability or rapidity of state changes, and responsiveness to treatment. Several investigators have incorporated these variables into systems for classifying the course of bipolar disorder (Angst et al., 1973; Kukopolos & Reginaldi, 1980; Roy-Byrne, Post, Uhde, Porcu, & Davis, 1985; Winokur & Clayton, 1967). For example, Angst and colleagues described a classification system based on the appearance of fully syndromal states, as well as subsyndromal symptoms (mild depression and hypomania). Kukopolos and Reginaldi revised this system by describing course patterns based on the sequencing of symptomatic and asymptomatic intervals (e.g., manic episodes followed by depressive episodes followed by asymptomatic intervals, vs. cycling without interepisode recovery). Akiskal (1996) presented a method of classification that views bipolar I disorder as an extreme within a broader bipolar spectrum. His conceptualization places greater emphasis on a patient's interepisode functioning than on the symptoms presented during acute episodes. Akiskal distinguishes classic bipolar I disorder from bipolar II disorder, which may be accompanied by an interepisodic cyclothymic temperament (i.e., biphasic dysregulation marked by cycling between short periods of hypomania and mini-depressions), and

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bipolar III, or pseudounipolar disorder, marked by recurrent depressive episodes with an underlying hyperthymic temperament (an enduring style of exuberance, overconfidence, grandiosity, and stimulus-seeking), and/or a family history of bipolar disorder. He also describes a subbipolar dysthymia marked by ongoing mild depressions with hypomanias that are evoked by antidepressant treatment. Evidence in favor of these distinctions is provided by Akiskal and colleagues (Akiskal; Akiskal & Akiskal, 1992). These systems classify patients according to episode patterning, although they differ in how much they emphasize the degree and type of interepisode recovery as a key feature of different forms of the disorder. A patient's symptoms during the intermorbid periods may be useful indicators of the level of chronicity and the degree of response to behavioral, psychosocial, or pharmacological interventions. Full remittance of symptoms occurs at 6 months in 73% of bipolar I patients who have experienced one or two previous episodes, and in 55% of those who are experiencing their first episode (Keller et al., 1986). Thus, much valuable information about clinical progress may be lost if one does not consider the patient's degree of remission from depressive or manic episodes. The systems also vary in the degree to which they distinguish patients with mixed affective symptoms (depression and mania, simultaneously) from those without such symptoms. Patients with mixed affective disorder appear to be at risk for rapid cycling, and may be candidates for anticonvulsant drug regimes (Keck & McElroy, 1996). 1 This study attempts to determine whether the course of bipolar disorder can be reliably categorized into subtypes using a number of the variables outlined by Goodwin and Jamison (1990). We examined 56 bipolar I patients with comprehensive course of illness data, collected retrospectively. Many patients had prolonged periods of hypomania and dysthymia between major episodes, and presented with mixed symptom constellations during one or more episodes. We address three questions. What variables define a particular course of illness in bipolar disorder? Can independent raters reliably agree on the classification of patients into these operationally defined course types? Can distinct course types be differentiated on traditional illness history variables, such as the number of prior episodes or hospitalizations, or the severity of symptoms during an acute period of illness (criterion validity)?

Method

Participants Participants were part of a larger longitudinal project investigating the role of family factors and interventions in the course of bipolar disorder (Mik1 Increasingly, antieonvulsants are being used as mood stabilizing agents for bipolar disorder patients. These agents are used as substitutes for, or in combination with, lithium carbonate. The most commonly used anticonvulsants are carbamazepine (Tegretol) and divalproex sodium (Depakote).

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lowitz, Frank, & George, 1996). During the first 4 years of study (1990-1994), 71 patients were recruited. A majority (n = 65) originated from hospitals in the Denver and Boulder area, including the University of Colorado Health Sciences Center, Centennial Peaks Hospital, Mapleton Center of Boulder Community Hospital, and Cedar House of Boulder County Mental Health Center. A smaller number (n = 6) originated from private outpatient clinics. Diagnosis Trained clinicians determined diagnoses based on the Structured Clinical Interview for DSM-Ill-R, Patient version (SCID-P; Spitzer, Williams, Gibbon, & First, 1988). Research staff members administered the SCID-P to patients either during a period of hospitalization, sometime shortly after discharge from the hospital or within 2 weeks of referral from an outpatient clinic, during or shortly following an acute period of illness. Study diagnosticians excluded from the study patients whose SCID-P responses suggested that they did not fulfill the DSM-III-R (APA, 1987) criteria for bipolar, manic, mixed, or depressive disorder within the preceding 3 months. Prior to administering the SCID-E diagnosticians were trained in the instrument using a four-step process. First, they were familiarized with the SCID-P items and instructions for administration. Next, they watched and rated videotapes of a trained diagnostician administering the instrument. Then, they practiced the interview with volunteer nonpatients. Finally, they rated a series of SCID-P videotapes from the present sample. Interrater reliability between study diagnosticians and a criterion rater (DJM) ranged from .69.72 (Cohen's K) for individual items on the SCID-E Exclusion Criteria All patients in the larger study were between the ages of 18 and 60, English speaking, and in frequent contact (at least 4 hours per week) with a family member (parent, spouse, sibling) living in the Denver and Boulder region. Exclusion criteria included evidence of comorbid neurological complications (e.g., closed head injury), mental retardation, or significant alcohol or substance abuse during the 6 months prior to the interview. Upon entry into the study, patients who were not already receiving medication from a community psychiatrist were referred to an appropriate provider. Psychiatrists treated all study patients with mood stabilizing medications (lithium carbonate, anticonvulsants, or combinations of these medications). Patients also received adjunctive antipsychotic, antidepressant, or anxiolytic agents as needed. Participant Characteristics This study included patients from the larger study for whom we could document a complete history of the disorder, from the age of onset until the acute episode marking their entry into the study. Of the participants in the larger longitudinal study (N = 71), we had complete episode information on 56 par-

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ticipants. There were 18 males (32%) and 38 females (68%). The sample's mean age of illness onset was 25.9 years (SD = 9.8); age at study entry averaged 36.3 (SD = 9.9); the mean level of education was 13.8 years (SD = 2.7); and socioeconomic class, ]based on the Amherst Modification (Watt, 1976) of Hollingshead and Redlich's (1958) criteria], was 2.7 (SD = 1.1).

Procedure Symptom assessment. Following the SC1D-P administration, the diagnostician administered the Schedule for Affective Disorders and Schizophrenia, Change Version (SADS-C; Spitzer & Endicott, 1978), which evaluated the patient's symptomatic functioning during the 3 months up to and including the index episode. The SADS-C, a 36-item structured interview, rates the duration and severity of depressive, manic, anxiety, and psychosis symptoms. Interrater reliabilities for SADS-C subscores ranged from .81 to .92 (intraclass rs, ps < .01), across 11 independent raters. For this study, depression and mania subscores from the SADS-C were used as criteria against which the course types that emerged from the retrospectively collected illness data were validated. SADS-C scores were not used to classify patients into course types. Psychiatric history. Once a patient was recruited into the study and had completed the SCID-P interview, additional demographic and illness history information was collected using a psychiatric and social history inventory, supplemented by medical records. We recorded the age at onset of bipolar disorder, dates and polarities of all prior mood disorder episodes, and the duration and severity of all interepisodic, subsyndromal periods (e.g., dysthymia, mixed symptoms, or hypomania). We also collected information on dates, duration, and locations of past hospitalizations and prior treatments, including psychotherapy, counseling, and pharmacotherapy. In cases where patient reports were regarded as unreliable, information was supplemented by data from the patient's parents or spouse. Life Charting Staff compiled the information collected from the SCID-R the medical records, and the psychiatric and social history inventory for entry into the Life Chart Program for Recurrent Affective IllnessesTM (Leverich & Post, 1997), a software program designed to graphically depict the course of illness, prior hospitalizations, and pharmacological and psychological treatments received by the patient over time. To enable each patient's course trajectory to be depicted by the program, we entered information about the onset and offset of all mood-disorder episodes (including the most recent study episode), interepisode periods, and hospitalizations for the period from the age of illness onset until entry into the larger study (mean interval = 10.1 years, SD = 8.9 years). The Life Chart ProgramTM rates the severity level of symptoms during the acute, prodromal, residual, and interepisodic phases of the illness. This is done on a 5-point scale designated as 0.0 (asymptomatic), 2.5 (mild symp-

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toms), 5.0 (moderate symptoms), 7.5 (severe symptoms), or 10.0 (extreme symptoms). Episode polarity is classified as either manic or depressed. Because this program does not allow for the graphing of manic and depressed symptoms simultaneously, mixed episodes are identified by alternating 5-day durations of manic and depressive symptoms. An episode is designated as mixed if the individual experienced fully syndromal manic and depressive symptoms concurrently or the individual experienced manic and depressive symptoms separately, but within the same day or week.

Development of the Classification of Bipolar Course Types (CBCT) Manual In developing the CBCT manual we used five of the eight course descriptors identified by Goodwin and Jamison (1990): severity of depressive, manic and mixed states, polarity of episodes, and duration of episodes. From these five course descriptors, we defined nine course of illness variables. These variables were the occurrence of a prior depressive episode at an extreme level (e.g., hospitalization for major depression and serious suicide attempt) for less than a year; the occurrence of a prior depressive episode at a severe level (e.g., loss of job during a depressive period because of poor performance) for less than a year; the occurrence of a prior manic episode at an extreme level (e.g., hospitalization for full-blown mania and utilization of life savings on a vacation) for less than a year; the occurrence of a prior manic episode at a severe level (e.g., delusions of grandeur and sleep for only 3 or 4 hours per night) for less than a year; the occurrence of prior depressive symptoms at a mild or moderate level (e.g., tiredness more often than usual and crying often) for greater than a year; the occurrence of prior depressive symptoms at a mild or moderate level for less than a year; the occurrence of prior hypomanic symptoms at a mild or moderate level (e.g., an observable increase in activity, energy, or irritability without deterioration in functioning) for greater than a year; the occurrence of hypomanic symptoms at a mild or moderate level for less than a year, and the occurrence of prior full-blown mixed episodes or subsyndromal mixed symptoms at any severity level or duration. These nine variables distinguish short and severe or extreme episodes of mania or depression from long periods of hypomania or dysthymia. None of the patients' records revealed the occurrence of fully syndromal manic or depressive episodes lasting more than 1 year. The criterion rater, Kalbag, trained independent raters to judge the presence or absence of each of these nine course features using five sample life charts. Two raters and the criterion rater then independently rated each of the study life charts (N = 56) as characterized by or not characterized by these nine variables. All raters were unaware of the specific DSM-II1-Rdiagnoses made at project entry. Discrepancies between the criterion rater and the independent raters were discussed and consensus judgments made for each of the 56 charts. Next, we created a matrix table using the nine decisions as column headings and the 56 subject entries as row headings. Using the final consensus ratings, we either entered a yes (if the feature occurred) or a no (if the feature did not occur)

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for each subject across nine variables. We were able to find seven distinguishable patterns of yes/no answers. These patterns were used to operationally define the presenting characteristics of seven different course types. Within each course type definition, either the nine variables had to occur (inclusion criterion), could possibly occur, or definitely could not occur (exclusion criterion; see Table 1). Using these presence and absence ratings, we developed a CBCT manual that provided inclusion and exclusion criteria for each of the seven course types (see Table 2). The same independent raters, trained to make the presence versus absence ratings, were also trained to rate course types using the manual. First, the raters practiced on the same five sample life charts used earlier. They were then asked to classify, based on the manual, each patient's retrospective course of illness (N = 56) into one of the seven proposed course types. The raters first determined if each patient's course of illness fit the specific inclusion criteria for the first subtype (classic subtype). If all the inclusion criteria were not met, or an exclusionary criterion was met, then the rater proceeded to the next course type description until criteria for one of the course types was fulfilled.

Results

Interrater Reliability There was a high degree of interrater agreement (94%) on 504 decisions about the occurrence of the course descriptor variables (K = .87, p < .0001) TABLE 1 DESCRIPTION OF COURSE TYPES BY NINE DECISIONS Course Types Decisions

C1

Mn

Mx

D-I

D-II

DM

MM

Extreme depressive episode for < 1 year Severe depressive episode for < 1 year Extreme manic episode for < 1 year Severe manic episode for < 1 year Mild/rood dysthymic symptoms for > 1 year Mild/mod dysthymic symptoms for < 1 year Mild/mod hypomanic symptoms for > 1 year Mild/mod hypomanic symptoms for < 1 year Mixed symptoms/episodes at any severity

+ + + + P . P -

+ + P

P P P P P . P +

P P P + P

+ + P P + P

P -

P -

P P P P + P P +

+ + P + P +

.

. P -

.

Notes. Cl: classic type; Mn: manic type; Mx: mixed type; D-I: depressive type I; D-II: depressive type l/; DM: depressive with mixed type; and MM: manic with mixed type; +: characteristic had to occur for that course type (inclusion criterion); - : characteristic could not occur for that course type (exclusion criterion); P: possible, or that the characteristic could occur but is not a classification requirement. For the C1, Mn, and MM types, a severe or extreme manic episode must have occurred. For the Mx, DM, and MM patterns, mixed symptoms at any severity or duration must have occurred. For the D-I, D-I/, and DM types, mild or moderate dysthymic symptoms must have occurred for > 1 year.

KALBAG ET AL.

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TABLE 2 OPERATIONALAND CLINICALDESCRIPTIONSOF SEVEN COURSETYPES Type

Operational Definition

Clinical Definition

b~clusion: manic and depressive episode Shows distinct full-blown manic and Classic type at the severe or extreme severity level, depressive episodes. No distinct N = 10 (18%) Exclusion: dysthymic or hypomanic mixed episodes. No evidence of symptoms at the mild or moderate long-term dysthymia or hypomania. severity level for > 1 year or mixed episodes at any severity level. Inclusion: at least one manic episode at Characterized by clear full-blown Manic type manic episodes. Remission from N = 13 (23%) the severe or extreme severity level. Exclusion: depressive episodes at the episodes is complete. No major depressive episodes. No evidence severe or extreme severity level, of long-term hypomania or dysthymic or hypomanic symptoms at the mild or moderate severity dysthymia, and no mixed episodes. level for > 1 year, or mixed episodes at any severity level. Mixed type Inclusion: at least one mixed episode at any severity level for at least 10 N = 15 (27%) days. Exclusion: dysthymic or hypomanic symptoms at the mild or moderate severity level for > 1 year.

Depressive type I N = 6 (11%)

Shows at least one distinct mixed episode. During this episode, depressive symptoms either occur concurrently with the manic symptoms or separately within the same day or week. No evidence of long-term hypomania or dysthymia symptoms.

Inclusion: dysthymic symptoms at the Characterized by long-term dysthymia mild or moderate severity level for > 1 year. Exclusion: depressive episodes at the extreme severity level, hypomanic symptoms at the mild or moderate severity level for > 1 year, or mixed symptoms at any severity level.

but there are no extreme depressive episodes. Major manic episodes can occur, but the underlying dysthymia continues after remission of manic symptoms. No evidence of mixed symptoms.

(continued)

listed in T a b l e 1. Further, the t h r e e raters a g r e e d o n the t y p e c l a s s i f i c a t i o n o f 8 8 % (K = .85, p < .0001) o f the patients. Patients w e r e c l a s s i f i e d as c l a s s i c (n = 10, 18% o f the s a m p l e ) , m a n i c (n = 13, 2 3 % ) , m i x e d (n = 15, 2 7 % ) , d e p r e s s i v e t y p e I (n = 6, 1 1 % ) , d e p r e s s i v e t y p e II (n = 4, 7 % ) , d e p r e s s i v e w i t h m i x e d (n = 7, 13%), a n d m a n i c w i t h m i x e d (n = 1, 2 % ) . T h e raters disc u s s e d e a c h d i s a g r e e m e n t and a r r i v e d at a g r o u p c o n s e n s u s rating.

Distribution o f the Subtypes T e n p a t i e n t s ' life charts w e r e c h a r a c t e r i z e d b y e x t r e m e or s e v e r e m a n i c and d e p r e s s i v e e p i s o d e s l a s t i n g less t h a n 1 year. T h e s e charts did n o t s h o w any

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TABLE 2 (Continued)

Type

Operational Definition

Clinical Definition

Depressive type II N = 4 (7%)

Inclusion: dysthymic symptoms at the Characterized by a long-term

Depressive with mixed type N = 7 (13%)

Inclusion: dysthymic symptoms at the Characterized by a long-term

mild or moderate severity level for > 1 year and mixed episodes or symptoms at any severity level. Exclusion: hypomanic symptoms at the mild or moderate severity level for < 1 year.

dysthymia and intermittent mixed episodes with or without manic episodes.

Manic with mixed type N = 1 (2%)

Inclusion: manic episode at severe or

Characterized by manic episodes, hypomanic symptoms for >1 year, and the presence of mixed episodes. No long-term dysthymia or major depressive episodes occur.

mild or moderate severity level for > 1 year and a depressive episode at the extreme severity level. Exclusion: hypomanic symptoms at the mild or moderate severity level for > 1 year or mixed episodes at any severity level.

extreme severitylevel and hypomanic symptoms at mild or moderate level for > 1 year, and mixed episodes at any severity level or duration. Exclusion: Depressive episodes at the extreme or severe level, or dysthymic symptoms at the mild or moderate level for > 1 year.

dysthymia with intermittent major depressive and manic episodes. Dysthymia continues after the remission of the full-blown mania or depression. Although both major depression and mania occur they do not occur together in a mixed state.

evidence o f h y p o m a n i c or d y s t h y m i c s y m p t o m s lasting greater than 1 year, although s o m e did show h y p o m a n i c and d y s t h y m i c s y m p t o m s for less than 1 year. This pattern o f s y m p t o m s describes the classic t y p e (see F i g u r e 1). T h e s e 10 patients c o u l d b e d i s t i n g u i s h e d f r o m 13 patients w h o experie n c e d f u l l - b l o w n m a n i c e p i s o d e s and d y s t h y m i c or h y p o m a n i c s y m p t o m s for less than 1 year, but w h o d i d not e x p e r i e n c e severe or e x t r e m e d e p r e s sive e p i s o d e s . T h e s e patients w e r e classified as h a v i n g a m a n i c c o u r s e t y p e (see F i g u r e 1). P a t i e n t s ' c o u r s e t y p e s identified as d e p r e s s i v e ( d e p r e s s i v e t y p e I, n = 6; d e p r e s s i v e t y p e II, n = 4; a n d d e p r e s s i v e w i t h m i x e d features, n = 7) w e r e all c h a r a c t e r i z e d b y d y s t h y m i c s y m p t o m s lasting l o n g e r than 1 year. T h e s e c o u r s e t y p e s c o u l d b e d i s t i n g u i s h e d f r o m e a c h other b y the p r e s e n c e o f e x t r e m e (i.e., h o s p i t a l i z e d ) d e p r e s s i v e e p i s o d e s (a r e q u i r e m e n t for classific a t i o n in the d e p r e s s i v e t y p e II pattern, but an e x c l u s i o n a r y criteria for classification in the d e p r e s s i v e t y p e I pattern); the p r e s e n c e o f m i l d or m o d e r a t e h y p o m a n i c s y m p t o m s for less than 1 y e a r (an e x c l u s i o n criteria for the d e p r e s s i v e with m i x e d f e a t u r e s type); or the p r e s e n c e o f m i x e d s y m p t o m s

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E.xg'eme A N

Moderate Mild AsymptornatJc

D p R

Moderate Severe Extreme

II

"

ii

Classic Subtype: Severe and extreme episodes of mania and depression

M A N

Extreme

Moderate Severe I Mild Asymptomati¢ Mild D Moderate Severe P Extreme R

II

U

!

I

s

Manic Subtype: Severe and extreme episodes of mania

A N

Severe Moderate Mild AsymptomatJc D Mild p Moderate R Severe ExVeme Mixed Subtype: Mixed episodes at any severity level

A

N

Severe

Moderate

M E~ I I Mild AsymptomalJc

D p

R

Mild Moderate Severe

I

I

~

I

II

I

I

I

Extmm

Depressive Type h Long-term dysthymic symptoms with severe depressive episodes FIG. 1. Life charts illustrating the seven course types found in this sample of bipolar patients (N = 56). Man = manic: Dpr = depression.

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METHOD FOR CLASSIFYING COURSE OF BIPOLAR DISORDER

M

Extreme

N

Moderate

A

Severe

- -

Mild Asymptornatlc D Mild p Moderate R

I

I

]

1

Severe

Extreme Depressive Type II: Long-term dysthymic symptoms with extreme depressive episodes

M

Ex'gerne

Ase E N

Dp R

I

Moderate

MiLd Asymptorna~c

Mild

Moderate

I

Severe Ex~eme

I

I

I

Depressive with Mixed Subtype: Long-term dysthymic symptoms with mixed episodes

N D

Moderate Mild

ksyrnptornatic Mild

Moderate

P

R

Severe Extreme

E

1

I

I

F1

Manic with Mixed Subtype: Manic episodes at severe or extreme level with mixed episodes, long-term hypomanic symptoms. FIG. 1. Continued

or episodes before, during, or after the dysthymic periods (the key inclusion criteria for the depressive with mixed features type). Additionally, 15 patients primarily experienced mixed symptoms with no long-term dysthymic symptoms (mixed type). One patient experienced extreme manic and prolonged hypomanic episodes, alternating with periods of mixed symptoms (manic with mixed type). Relationships between Course ~,pes and Patient Attributes We wished to evaluate the concurrent validity of these course types through examining their relationship to demographic variables (patient's sex or age) and traditional course of illness variables, such as patients' ages at illness onset, number of prior DSM-III-R manic and depressive episodes (as

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TABLE 3 DESCRIPTIVE STATISTICS BY COURSE TYPE

Variables N % female Age at illness onset, years Age at study entry, years No. of prior hospitalizations No. of prior episodesa No. of prior manic episodes No. of prior depr. episodes

CI 10 90% 25.4 (11.7) 36.2 (10.4) 3.4 (2.7) 5.1 (4.7) 2.4 (2.2) 2.7 (3.3)

Mn

Mx

13 15 46% 80% 21.3 27.3 (4.9) (12.0) 34.3 35.1 (10.1) (tl.2) 4.8 1.7 (4.4) (2.4) 5.7 2.2 (3.6) (3.5) 3.8 1.0 (3.4) (2.3) 1.8 1.2 (2.1) (1.4)

D-I

D-II

6 4 67% 50% 26.0 22.3 (5.5) (6.6) 36.0 37.8 (11.3) (10.2) 2.3 2.8 (2.7) (2.1) 2.0 4.0 (1.5) (3.2) 1.0 0.5 (1.3) (0.6) 1.0 3.5 (0.6) (2.6)

DM

MM

7 71% 33.3 (10.9) 42.0 (5.2) 1.1 (1.7) 1.3 (1.4) 0.9 (1.5) 0.4 (0.5)

1 0% 33.0 (r~/a) 35.0 (n/a) 0 (n/a) 2.0 (n/a) 1.0 n/1 1.0 (n/a)

Notes. Standard deviations are in parentheses. CI: classic type; Mn: manic type; Mx: mixed

type; D-I: depressive type I; D-II: depressive type II; DM: depressive with mixed type; and MM: manic with mixed type; depr: depressed. a The sum of all manic and depressive episodes that occurred prior to entry into the larger treatment project.

revealed by the SCID diagnostic interview, which relied exclusively on patient reports), the number of prior hospitalizations, and s y m p t o m severity during the acute illness episode that marked entry into the larger treatment study (based on an independently conducted S A D S - C interview). Means and standard deviations for each of several demographic and illness history variables are presented in Table 3. Our sample size (N = 56) precluded extensive comparisons o f different pairings of the seven course types. Thus, to determine whether there were differences a m o n g the course types on these criterion variables, we constructed two planned comparison contrasts based on the course descriptor distinctions outlined in Table 1. In order to increase the reliability of these contrasts, we excluded the one course grouping that had a single m e m b e r (the manic with mixed s y m p t o m type). First, we compared patients with manic profiles--those for w h o m a past history of a severe or extreme manic episode was the key inclusionary criterion (the classic type and the manic type, n = 2 3 ) - - t o those for w h o m these episodes could occur, but were not a classification requirement (the mixed, depressive type I, depressive type II, and depressive with mixed types, n = 32). Second, we compared patients with mixed profiles--those for w h o m a history o f mixed s y m p t o m s was the key inclusionary criterion (the mixed and

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depression with mixed types, n = 22)--to those for whom mixed symptoms were proscribed for category inclusion (the classic, manic, depressed type I, and depressed type I! types, n = 33). Other contrasts were considered (e.g., patients with vs. without periods of dysthymia that lasted greater than 1 year), but these contrasts were redundant with the two primary contrasts chosen. We reasoned that patients with manic profiles would be more frequently hospitalized due to the more disruptive nature of their behavior. We also expected them to display more severe manic symptoms during an acute illness episode, and for the mixed profile patients to display more severe depressive symptoms. Furthermore, we predicted differences in course types by sex, such that the group primarily characterized as manic would include a greater proportion of men, whereas the group characterized by mixed periods would include a greater proportion of women (e.g., Liebenluft, 1996). Because of the small number of patients, these statistical comparisons must be viewed as preliminary and exploratory. The planned contrasts (manic vs. other; mixed vs. other) were nonsignificant for sex of the patient and age at study entry (for all, p > .10). However, the patients with mixed symptom profiles had later ages at illness onset (M = 29.2 years, SD = 11.8) than those without prior mixed symptoms [M = 23.5 years, SD = 7.6; F(1, 48) = 5.15, p < .05]. Further, the patients with manic profiles had more prior hospitalizations (M = 4.2, SD = 3.8) than those not so classified [M = 1.8, SD = 2.2; F(1, 48) = 5.7, p < .025], 2 and more lifetime episodes of bipolar illness [for the patients with manic profiles, M = 5.4, SD = 4.0; for the patients without manic profiles, M = 2.2, SD = 2.8; F(1, 49) = 9.25, p < .005]. In contrast, patients who had had mixed symptom profiles had fewer hospitalizations (M = 1.5, SD = 2.2) than those without mixed profiles [M = 3.7, SD = 3.4; F(1, 48) = 4.3, p < .05]. When considering manic and depressive episodes separately, manic profile patients had had more lifetime DSM-III-R manic episodes (M = 3.2, SD = 2.98) than those not so classified [M = 0.9, SD = 1.77; F(1, 49) = 10.95, p < .002], but a comparable number of prior DSM-III-R major depressive episodes [F(1, 49) = 1.57, p > .10]. However, patients with mixed profiles had had fewer lifetime DSM-III-R major depressive episodes (M = 0.95, SD = 1.25) than those without prior mixed symptoms [M = 2.15, SD = 2.46; F(1, 49) = 5.6, p < .025]. The mixed profile patients did not differ on prior manic episodes from those not so classified [F(1, 49) = 1.99, p > .10]. Contrary to our expectations, the manic and non-manic profile patients could not be distinguished on the severity of manic symptoms displayed during the acute episode prior to entry into the study [F(1, 49) = 0.02, p > .10]. However, manic profile patients had less severe depression severity scores during this episode than patients not so classified [F(1, 49) = 11.75, p < .002]. No differences on mania or depression severity scores during the acute epi2 Data on number of prior hospitalizations and age at illness onset were missing for one patient.

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sode were observed among patients with versus without mixed symptom profiles (for both, p > . 30). 3

Discussion The course of bipolar disorder has been known to be variable. Systems of classification that capture this variability would be quite useful in selecting patients for behavioral or pharmacologic treatment regimes, and in evaluating the efficacy of these regimes. Knowing that a patient has followed a particular course of illness may inform treatment planning for cognitivebehavioral, psychoeducational or pharmacological approaches to his or her outpatient management. Various attempts have been made to classify the variability in the course of bipolar disorder (e.g., Akiskal, 1996; Angst et al., 3973; Kukopolos & Reginaldi, 1980). This study reflects one such effort. We have developed a course classification system that takes into account features of the disorder that have received little attention in prior classification systems: the presence of prolonged interepisode dysthymic or hypomanic periods, the presence of mixed episodes or symptoms, and severity and duration distinctions among episodes of mania or depression. This system was developed based on the examination of the courses of illness of 56 bipolar I patients, studied retrospectively from the time of illness onset until entry into a psychosocial treatment study. Data on the course of the disorder were based on structured interviews with the patient about prior illness episodes, psychiatric and social history schedules (which included information from family members), and all available medical records. From these data, we identified seven course-of-illness subtypes. These were derived from nine presence versus absence course-indicator variables (e.g., the presence vs. absence of mixed symptoms). Independent raters were able to classify the 56 patients into these seven categories with a high degree of reliability. Using this system, we documented some heterogeneity in the course of the disorder often described in the clinical literature, but not always operationalized within research studies. Interestingly, only 38% of the sample could be described as showing the classic bipolar I pattern, marked by fully syndromal manic and depressive episodes and periods of remission between episodes. Fully 43 % of the sample had significant mixed affective symptoms during the retrospective period. Moreover, 32% of the sample showed persistent (i.e., at least 1 year) dysthymic or, in one case, hypomanic symptoms in between major episodes of depressive, manic, or mixed affective illness. 3 The omnibus F statistics for the univariate comparisons of the six course types were as follows: for age at illness onset, F(5, 48) = 1.6, p > . 10; number of prior hospitalizations, F(5, 48) = 2.02, p < .10; number of prior mood disorder episodes, F(5, 49) = 2.7, p < .05; number of prior manic episodes, F(5, 49) = 2.95, p < .025; number of prior depressive episodes, F(5, 49) = 1.97, p < . 10; depression symptoms during the index episode, F(5, 49) = 3.17, p < .02; manic symptoms during the index episode, F(5, 49) = 0.26, p > . 10).

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The rate of patients who never fully recovered from their major episodes (32%) is comparable to the rate of 27% found by Keller et al. (1986) in a sample of 155 major affective disorder patients. However, it is substantially lower than that found by Gitlin and colleagues (Gitlin, Swendsen, Heller, & Hammer, 1995) in a prospective follow-up of bipolar outpatients (N = 82). In that study, only 17% of the patients were found to be euthymic or only minimally symptomatic throughout a 5-year follow-up. It is possible that we underestimated the degree of interepisode morbidity among patients in this sample due to our reliance on retrospective data. In any case, a productive goal for behavioral treatments with this population would be to address the residual hypomanic or dysthymic symptoms remaining after major affective episodes, as well as the psychosocial impairments (e.g., occupational dysfunction) associated with these symptom states. Because of the nature of our decision rules, we did not identify a separate rapid cycling subtype of bipolar disorder. In fact, any of the seven course types could have been characterized by rapid cycling, which is simply defined as the presence of four or more episodes of mania, depression, mixed illness, or hypomania in a single year (APA, 1994). In this sample, only one patient (2% of the sample) could be described as a rapid cycler. This rate is lower than other studies (13% to 20%; Calabrese, Fatemi, Kujawa, & Woyshville, 1996). The low rate probably reflects the fact that we recruited relatively unambiguous bipolar I patients into the larger treatment study and excluded those with recent alcohol or substance abuse or dependence. It is also possible that rapid cyclers were more likely to refuse participation in the larger study. Our methods for distinguishing broader illness types (e.g., patients who had vs. had not experienced at least one severe or extreme manic episode; patients who did and did not have mixed symptom profiles) were largely supported by group comparisons on traditional course of illness variables. Specifically, patients with manic symptom profiles (classic and manic types) had more prior hospitalizations, and less severe accompanying depressive symptoms during an acute illness episode, than those without manic profiles. Patients with mixed symptom profiles (mixed and depressive with mixed types) had fewer hospitalizations and later ages at illness onset than those without these profiles. However, our sample size was relatively small (N = 56), which limited our power to detect statistically reliable differences between the course types. Hypothetically, course type differences on age or sex ratios might have emerged in a larger sample, in which each category was well represented. Alternatively, future research may reveal that certain distinctions, although reliable, have limited concurrent or predictive validity. Thus, our current findings, though promising, do not allow us to draw firm conclusions about the discriminant validity of each proposed course type. The lack of group differences in patient's sex requires further examination. It is tempting to conclude that sex differences in the course of bipolar disorder become less salient when data on the prior course of illness are collected systematically from different information sources, and over relatively long

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periods of illness. However, given that the current classification system was not developed with the explicit objective of distinguishing male and female bipolar patients, the lack of sex differences, observed post-hoc, should not be overinterpreted. Moreover, our study only concerned bipolar I patients. The bipolar II subtype is more common among female patients, and the relative proportion of depressive to manic episodes is higher among women (Liebenluft, 1996). Thus, the exclusion of bipolar II patients may have reduced our power to detect sex differences. The classification system and the data on which it was based are limited in a number of ways. First, as discussed above, our judgments of prior illness course were based on retrospective reports, which are subject to recall biases. Validation of the current system awaits investigations of the consistency between course of illness classifications based on prospectively versus retrospectively collected data. This is a key point given the episodic nature of bipolar disorder, and the ways in which patients' symptoms can shift over time (e.g., Keller et al., 1986; Post, 1992). It is conceivable that patients who have shown mixed symptom presentations in the past will not do so once placed on the proper pharmacotherapy regime. Likewise, if patients who have shown a primarily depressive bipolar course of illness undergo a series of severe life events that disturb sleep/wake rhythms (e.g., birth of a baby; see Malkoff-Schwartz et al., 1998), or are placed on an antidepressant that evokes manic symptoms, they may begin to shift toward the classic or mixed symptom bipolar course types. Prospective validation studies that evaluate the temporal stability of these course types are clearly needed. Second, our system classifies patients only according to symptom criteria. A patient's course of illness can also be understood in terms of social and occupational functioning, time to recovery from illness episodes, and cycle length. These factors should be taken into account when evaluating the response of patients to treatments. Third, although the 56 patients could all be classified into one of seven course types, we cannot conclude that this system thoroughly covers the various symptomatic manifestations of bipolar disorder in the general population. This is partly an issue of sample size: with a much larger sample, many other combinations of our dichotomous variables might have emerged and defined other course types. It is also likely that different course patterns would have resulted from the inclusion of "soft spectrum" as well as "hard spectrum" bipolar patients (Akiskal, 1996). For example, including patients with bipolar III or cyclothymic disorder would have introduced course patterns marked by ongoing hyperthymic behavior and/or rapid alternations between brief depressive and hypomanic states. Inclusion of such patients might have led to different conclusions than we have drawn here about the frequency of various course patterns in bipolar disorder. Our classification system deserves further investigation in psychosocial or pharmacological treatment studies of bipolar I patients. Among its various research applications are the mirror-image strategies for analyzing treatment-

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outcome data. One could classify the course patterns of a group of patients before a behavioral treatment challenge or a comparison treatment and again in the year or years following these challenges. If the behavioral treatment has been successful, patients whose prior course of illness was characterized by long periods of interepisode dysthymia may shift to course types not characterized by significant residual symptoms, or patients with extreme depressive or manic episodes may begin to have recurrences of lesser severity (i.e., episodes not requiring hospitalization) following treatment. Certain treatment decisions for bipolar patients are routinely made on the basis of prior illness course features as well as presenting symptoms (e.g., the introduction of an antidepressant or cognitive therapy for patients with interepisode dysthymia, or anticonvulsants for mixed episode patients). The present system offers the clinician a method for predicting a patient's subsequent course of illness, which may be useful in informing such treatment decisions. Specifically, certain course types may require different emphases within cognitive, interpersonal, or behavioral models. For example, patients with primarily euphoric-manic presentations are particularly prone to medication nonadherence (Jamison & Akiskal, 1983). Therefore, cognitive or psychoeducational approaches to these patients may need to emphasize dysfunctional assumptions regarding the illness and its treatment (e.g., "Medications take away my emotions, and I cannot enjoy life unless I experience the highs"). In contrast, cognitive behavioral approaches to the patient with longterm depressive symptoms may require a greater focus on pessimistic attributions and behavioral activation. Determining whether the placement of patients into one of the seven proposed course types actually aids clinical decision-making in practice, and whether the success of psychosocial treatments can be measured by variations over time in these course patterns, are important directions for future research.

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