Longitudinal Course of Bipolar I Disorder Duration of Mood Episodes

ORIGINAL ARTICLE Longitudinal Course of Bipolar I Disorder Duration of Mood Episodes

David A. Solomon, MD; Andrew C. Leon, PhD; William H. Coryell, MD; Jean Endicott, PhD; Chunshan Li, MA; Jess G. Fiedorowicz, MD; Lara Boyken, BA; Martin B. Keller, MD

Context: The phenomenology of bipolar I disorder af- covered from their mood episodes within 1 year of on- fects treatment and prognosis. set. The probability of recovery was significantly less for an episode with severe onset (psychosis or severe psy- Objective: To describe the duration of bipolar I mood chosocial impairment in week 1 of the episode) (hazard episodes and factors associated with recovery from these ratio [HR]=0.746; 95% confidence interval [CI], 0.578- episodes. 0.963; P=.02) and for subjects with greater cumulative morbidity (total number of years spent ill with any mood Design: Subjects with Research Diagnostic Criteria bi- episode) (HR=0.917; 95% CI, 0.886-0.948; PϽ.001). polar I disorder were prospectively followed up for as long Compared with the probability of recovery from a ma- as 25 years. The probability of recovery over time from jor depressive episode, there was a significantly greater multiple successive mood episodes was examined with probability of recovery from an episode of mania survival analytic techniques, including a mixed-effects (HR=1.713; 95% CI, 1.373-2.137; PϽ.001), hypoma- grouped-time survival model. nia (HR=4.502; 95% CI, 3.466-5.849; PϽ.001), or mi- nor depression (HR=2.027; 95% CI, 1.622-2.534; Setting: Five US academic medical centers. PϽ.001) and, conversely, a significantly reduced probability of recovery from a cycling episode (switching from Participants: Two hundred nineteen subjects with bi- one pole to the other without an intervening period of polar I disorder. recovery) (HR=0.438; 95% CI, 0.351-0.548; PϽ.001).

Main Outcome Measures: Level of psychopathol- Conclusions: The median duration of bipolar I mood ogy was assessed with the Longitudinal Interval Fol- episodes was 13 weeks, and the probability of recovery low-up Evaluation every 6 months for the first 5 years was significantly decreased for cycling episodes, mood of follow-up and annually thereafter. episodes with severe onset, and subjects with greater cumulative morbidity. Results: The median duration of bipolar I mood episodes was 13 weeks. More than 75% of the subjects re- Arch Gen Psychiatry. 2010;67(4):339-347

IPOLAR I DISORDER IS USU- as recovery from a mood episode.4 How- Author Affiliations: UpToDate, ally characterized by recur- ever, a limitation of hypothesis testing with Inc, Waltham, Massachusetts rent mood episodes.1 It is standard survival analytic techniques is (Dr Solomon); Department of Psychiatry and Human important to follow up with that they assume independence among ob- Behavior, The Warren Alpert subjects over many years to servations and therefore can include only Medical School of Brown studyB the phenomenology of these epi- 1 mood episode per subject. As a conse- University, Providence, Rhode sodes given that bipolar I disorder has a quence, these techniques preclude study- Island (Drs Solomon and Keller mean (SD) age at onset of 18.2 (11.6) ing the effects of successive mood epi- and Ms Boyken); Department of years2 and the risk of having mood episodes. Rather, the investigator must Psychiatry, Weill Cornell sodes remains relatively high for at least arbitrarily select only 1 of many mood epi- Medical College (Dr Leon and 40 years after onset.3 sodes, such as the most recent. This ap- Mr Li) and New York State Another issue to consider is whether the proach fails to characterize the course of Psychiatric Institute data analytic procedures can use all of the an episodic and recurrent illness such as (Dr Endicott), New York; and Department of Psychiatry, Roy relevant data rather than selected por- bipolar I disorder and limits the general- J. and Lucille A. Carver College tions. Until recently, survival analysis has izability of the results. of Medicine, University of Iowa been the primary means of analyzing lon- In the last 30 years, statisticians have Hospitals and Clinics, Iowa City gitudinal data in psychiatry, particularly developed analytic methods that can ex- (Drs Coryell and Fiedorowicz). when examining the time to an event such amine correlated observations, such as

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 multiple within-subject mood episodes, in one model. netic hypotheses were tested), knowledge of one’s biological These statistical techniques account for the correlation parents, and no evidence that the intake mood disorder was among multiple mood episodes and at the same time al- secondary to a general medical condition. The study was ap- low the number of episodes per subject to vary widely, proved by the institutional review board at each study site, and thus making it possible to estimate the cumulative effect subjects provided written informed consent after receiving a complete description of the study. of prior mood episodes and better understand the over- The sample for our study included 219 subjects who (1) met all course of illness. Examples of these relatively new ana- Research Diagnostic Criteria9 for a major mood episode at the 5 lytic methods include intensity analyses, frailty mod- time of enrollment, (2) were diagnosed at study intake or dur- els,6 and mixed-effects grouped-time survival models.7 ing prospective follow-up as having either bipolar I disorder or To our knowledge, only 1 prior study3 has used one schizoaffective disorder, mainly affective subtype, (3) recov- of these new methods to analyze recovery from mul- ered from the mood episode present at study intake, and (4) even- tiple, within-subject, prospectively observed bipolar I tually had at least 1 recurrent mood episode. (Research Diag- mood episodes. The median duration of all mood epi- nostic Criteria9 and DSM-IV criteria10 for bipolar I disorder are 9 sodes was 4.2 months. No results were given for the av- identical. Research Diagnostic Criteria for schizoaffective dis- erage duration of the different types of mood episodes order, mainly affective subtype, are very similar to the DSM-IV criteria10 for bipolar I disorder. The inclusion of subjects with observed, which included major depression, minor de- schizoaffective disorder in this study is consistent with other lon- pression, mania, hypomania, cycling, and mixed. gitudinal studies of bipolar I disorder.3,11,12) Our study addresses these 2 methodological issues and Of the 219 subjects, 156 (71%) were diagnosed at study in- the need for additional studies by applying a mixed- take as having bipolar I disorder, 25 (11%) were diagnosed at effects grouped-time survival model to data from the on- study intake as having unipolar major depressive disorder but going National Institute of Mental Health Collaborative subsequently had at least 1 episode of mania during prospec- Program on the Psychobiology of Depression–Clinical tive follow-up, 14 (6%) were diagnosed at study intake as hav- Studies (Collaborative Depression Study). The Collabo- ing bipolar II disorder but subsequently had at least 1 episode rative Depression Study began prospectively following of mania during prospective follow-up, and 24 (11%) were di- subjects with bipolar I disorder in 1978,8 and up to 25 agnosed at study intake as having schizoaffective disorder, mainly affective subtype. years of follow-up data are now available for analysis. The methodological strengths featured by this observational study include the use of direct subject interviews, stan- ASSESSMENTS AND PROCEDURES dardized diagnostic and follow-up instruments, fre- quent follow-up assessments, careful characterization of At study intake, raters interviewed subjects about their cur- the different types of mood episodes observed, and length rent and past psychiatric history using the Schedule for Affec- of prospective follow-up. tive Disorders and Schizophrenia.13 Raters also reviewed medi- Our results describe the duration of bipolar I mood cal records and, whenever feasible, interviewed other informants. episodes. Initially, time to recovery was estimated with- Diagnoses were then made according to Research Diagnostic 9 out regard to mood episode type, ie, the different types Criteria. of episodes were analyzed collectively. Next, time to re- After study intake, raters assessed the level of psychopa- covery was estimated for each type of mood episode, in- thology through direct interviews conducted every 6 months for the first 5 years of the study and annually thereafter using cluding major depression, minor depression, mania, hy- variations of the semi-structured Longitudinal Interval Fol- pomania, cycling, and mixed. low-up Evaluation.14 Subjects were prospectively followed up Finally, a mixed-effects model examined the magni- for as long as 25 years. tude of the association between hypothesized clinical pre- At each assessment, the interviewer rated the weekly level of dictors and the probability of recovery from a mood epi- psychopathology for each mood syndrome that occurred since sode. The predictors included type of mood episode, the time of the last interview and assigned a separate weekly score severe onset of mood episode (psychosis or severe psy- for each mood syndrome. To accomplish this, the rater first iden- chosocial impairment in week 1 of the episode), num- tified chronological anchor points such as holidays to assist the ber of prior mood episodes, and cumulative morbidity subject in remembering those times when significant clinical im- (total number of years spent ill with any mood epi- provement or deterioration occurred. Whenever possible, cor- roborative data were obtained from medical records. sode). These variables were selected for testing because Level of psychopathology for mania or major depression was they are characteristic of all bipolar I mood episodes and quantified on a 6-point scale in which a rating of 1 corre- are routinely assessed during the initial clinical evalua- sponded to no symptoms and 6 indicated meeting full criteria tion of patients. for the disorder along with psychosis or extreme impairment in functioning. For minor depression or hypomania, level of METHODS psychopathology was quantified on a 3-point scale (fewer symptoms were required to meet criteria for these disorders). Consistent with Research Diagnostic Criteria,9 recovery from SUBJECTS a mood episode was defined as at least 8 consecutive weeks either with no symptoms of major depression, minor depression, ma- From 1978 to 1981, the Collaborative Depression Study re- nia, and hypomania or with only 1 or 2 symptoms of a mild cruited patients receiving treatment for mood episodes at aca- degree and no impairment of psychosocial functioning. Dur- demic medical centers in Boston, Massachusetts; Chicago, Il- ing a mood episode, the weekly level of psychopathology may linois; Iowa City, Iowa; New York, New York; or St Louis, have varied anywhere between no symptoms to meeting full Missouri. Inclusion criteria included age of at least 17 years, criteria. For example, a major depressive episode may have in- IQ greater than 70, ability to speak English, white race (ge- cluded periods of euthymia (lasting Ͻ8 consecutive weeks) or

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 minor depression in addition to those weeks in which the sub- 5 mood episodes per subject that began after recovery from the ject met full criteria. Similarly, a manic episode may have in- intake mood episode. The observations within each of the 5 cluded periods of euthymia (lasting Ͻ8 consecutive weeks) or Kaplan-Meier analyses were independent because each sub- hypomania. ject had only 1 of each successive episode number (eg, first epi- An episode of minor depression was distinguished from par- sode). Based on the small number of mood episodes beyond tial remission of major depression in that the symptoms of a the fifth prospective recurrence, especially at longer follow-up minor depressive episode never rose to the level of major de- periods, we chose to not analyze episodes beyond the first 5 pression from onset to offset of the minor depressive episode. mood episodes. The intake mood episode was also excluded If at any point during a minor depressive episode the subject from these analyses because it was previously described else- met criteria for major depression, the entire episode was con- where19 and was not entirely prospective (subjects enrolled in sidered to be one of major depression. Hypomania was distin- the Collaborative Depression Study after onset of the intake guished from partial remission of mania in a similar manner. mood episode). Thus, all mood episodes included in these Recurrence or onset of a new mood episode was defined as analyses were observed prospectively from the time they the reappearance of major depression meeting full criteria for at commenced. least 2 consecutive weeks, mania meeting full criteria for at least Survival time (duration of mood episode) was defined as the 1 week, minor depression at the definite level for at least 2 con- number of weeks until recovery from the episode, beginning secutive weeks, or hypomania at the definite level for at least 1 with the first week of the episode. The survival analyses esti- week. Recurrence of a mood episode occurred only after the in- mated the cumulative probability of recovery over the course dividual had first recovered from the preceding mood episode. of follow-up. The survival time ended with recovery from the mood episode or, for censored cases, the end of the follow-up TYPES OF MOOD EPISODES period (25 years), withdrawal from the study, or death. In es- timating the rate of recovery, the analyses made use of all avail- Mood episodes were classified empirically within 1 of 8 differ- able data from all subjects, including the incomplete informa- ent categories, beginning with the categories of major depres- tion from censored cases. These analyses also accounted for the varying lengths of follow-up for different subjects. sion, minor depression, mania, hypomania, and mixed epi- 29 sode. Minor depression was defined as depressed mood A mixed-effects grouped-time survival model estimated the accompanied by 2 or more other symptoms, without psycho- magnitude of the association between various clinical predic- sis or the full depressive syndrome that characterizes major de- tors and the probability of recovery over time. The predictors pression, for at least 2 weeks. A mixed episode was defined as included mood episode type (described earlier), severe onset major depression or minor depression concurrent with mania of mood episode, number of prior mood episodes, and cumu- or hypomania throughout the entire episode, with at least 1 ma- lative morbidity. Severe onset of mood episode was defined such jor pole (major depression or mania) present at some point dur- that in week 1 of the episode, the subject met full criteria for ing the episode. major depression or mania along with psychosis or extreme im- In addition, we empirically defined 3 categories of cycling pairment in functioning. Number of prior mood episodes in- mood episodes because of their prevalence in this study and cluded only those episodes observed during prospective follow- because of their prevalence and prognostic significance in pre- up, beginning with the intake mood episode and ending with vious studies.15-27 Major cycling was defined as alternating pe- the mood episode immediately prior to the episode that was riods of depression (major depression or minor depression) and analyzed. Cumulative morbidity was defined as the total num- mood elevation (mania or hypomania), immediately contigu- ber of years spent ill with any type of mood episode during pro- ous with each other or separated by less than 8 consecutive weeks spective follow-up, beginning at study intake and ending at the with euthymia. In addition, at least 1 major pole (major de- week prior to onset of the mood episode that was analyzed. pression or mania) was present at some point during the epi- The mixed-effects model accounted for the correlation among sode. Mixed major cycling was defined as an episode of major multiple, within-subject mood episodes. In this grouped-time cycling that at some point also included a mixed state, ie, a pe- survival model, the mood episode durations were categorized riod with concurrent depression and mood elevation. (These as follows: 1 to 2, 3 to 4, 5 to 13, 14 to 26, 27 to 39, 40 to 52, mixed states were distinguished from and not synonymous with 53 to 104, and longer than 104 weeks. It was implicitly as- the mixed episodes defined earlier). Minor cycling was de- sumed that the hazard (likelihood of recovery) was constant fined as alternating periods of hypomania and minor depres- within any one categorized time interval. The mixed model also sion, immediately contiguous with each other or separated by calculated an intraclass correlation coefficient, which esti- less than 8 consecutive weeks with euthymia. mated the within-subject consistency in duration of mood episodes, across multiple episodes (without regard to mood episode type). Each statistical test used a 2-tailed ␣ level of .05. TREATMENT

The Collaborative Depression Study is an observational study RESULTS in that treatment is not assigned by design and not controlled by anyone connected with the study. Over time, the intensity SUBJECTS AND LENGTH OF FOLLOW-UP of treatment varied within subjects as well as between subjects. The type and dose of all prescribed somatic treatment were collected with the Longitudinal Interval Follow-up Evalua- Table 1 displays the sociodemographic and clinical char- tion14 and corroborated with available medical records. Our re- acteristics of the sample at study intake. The mean (SD) sults describe the somatic treatment subjects received during length of prospective follow-up was 17.3 (7.9) years, and episodes of major depression and mania. the median (range) was 20 (0.5-25) years. Of the 219 subjects, 196 (90%) were followed up for at least 5 years, DATA ANALYTIC PROCEDURES 169 (77%) for at least 10 years, 144 (66%) for at least 15 years, and 122 (56%) for at least 20 years. Attrition re- The Kaplan-Meier product-limit method28 estimated the cu- sulted from withdrawal of consent, an inability to locate mulative probability of recovery over time from each of the first or contact the subject, and death.

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 sodes comprised 768 of the 1208 mood episodes (64%). Table 1. Sociodemographic and Clinical Characteristics There were 219 subjects who had at least 1 recurrent mood at Study Intake for 219 Subjects With Bipolar I Disorder episode. Based on Kaplan-Meier estimates, 89% recovered from the first recurrent episode within 2 years of Characteristic Value onset of the episode. Of the 181 subjects with a second Age, mean (SD), y 37 (13) recurrent episode, 85% recovered from that episode within Sex, No. (%) 2 years. Of those with a third or fourth recurrent epi- Male 97 (44) Figure Female 122 (56) sode, 87% recovered within 2 years. The shows Marital status, No. (%) the corresponding survival curves for the duration of the Never married 84 (38) first 5 recurrent mood episodes based on cumulative re- Married or live together 85 (39) covery probabilities (Kaplan-Meier estimates). The 5 Divorced, separated, or widowed 50 (23) curves are similar, indicating that time to recovery in the a Socioeconomic status, No. (%) sample as a whole was consistent across multiple mood I 8 (4) episodes. II 32 (15) III 69 (32) The quartiles for duration of mood episode for each IV 63 (29) of the first 5 prospectively observed mood episodes were V 47 (21) also examined. Overall, across the entire set of these first Intake medical center, No. (%) 5 mood episodes, 25% of the subjects recovered within Boston, Massachusetts 34 (16) 5 weeks of onset of the episode (ie, the first quartile), 50% Chicago, Illinois 43 (20) of the subjects recovered within 13 weeks of onset (ie, Iowa City, Iowa 62 (28) New York, New York 31 (14) the median), and 75% recovered within 38 weeks (ie, the St Louis, Missouri 49 (22) third quartile). Status at intake, No. (%) Inpatient 196 (89) DURATION OF EACH TYPE OF MOOD EPISODE Outpatient 23 (11) Polarity of mood state at study intake, No. (%) Another set of analyses examined time to recovery from Mania 142 (65) Table 3 Major depression 62 (28) each type of bipolar I mood episode. shows the Mixed 15 (7) quartiles for the duration of the different types of mood Psychosis, No. (%) episodes. The median duration of major depressive epi- Present 121 (55) sodes, the most common type, was 15.0 weeks (SE, 1.1 Absent 98 (45) weeks). Recovery from 75% of the major depressive epi- b Global Assessment Scale score, mean (SD) 32 (11) sodes occurred within 35.0 weeks (SE, 3.7 weeks) of on- Age at onset for first lifetime 24 (10) mood episode, mean (SD), yc set of the episode. No. of mood episodes prior The median duration of major cycling episodes was to intake episode, No. (%) approximately 3 to 14 times longer than that of epi- 0 27 (12) sodes of pure depression or pure mood elevation, and the 1 20 (9) median duration of mixed major cycling episodes was ap- 2 26 (12) Ն proximately 4 to 20 times longer. One-fourth of the mixed 3 146 (67) major cycling episodes lasted more than 7 years (368.0 a Based on the Hollingshead-Redlich scale, with I indicating the highest weeks [SE, 104.7 weeks]). socioeconomic status and V indicating the lowest.30 The percentages do not sum to 100 because of rounding. CYCLING MOOD EPISODES b The range for the Global Assessment Scale is 1 to 100; higher scores indicate less psychopathology and better psychosocial functioning.31 c Major depression, minor depression, mania, or hypomania. The 304 cycling mood episodes (182 major cycling, 94 mixed major cycling, and 28 minor cycling) were composed of 4 possible component mood states: depression DURATION OF MOOD EPISODES ANALYZED (major or minor depression), mood elevation (mania or WITHOUT REGARD TO MOOD EPISODE TYPE hypomania), mixed state (concurrent depression and mood elevation), and euthymia lasting less than 8 con- A total of 1208 mood episodes were observed during fol- secutive weeks. During these cycling episodes, the mean low-up. The median number of mood episodes per sub- (SD) durations were 84 (160) weeks (median, 23 weeks) ject was 4 (range, 1-21). The mean (SD) number of epi- for depression, 28 (76) weeks (median, 7 weeks) for mood sodes per subject was 5.5 (4.6), and the mean (SD) elevation, 8 (52) weeks (median, 0 weeks) for mixed states number of episodes per subject per year of follow-up was (ie, more than half the cycling episodes did not include 0.4 (0.3). The mean (SD) percentage of follow-up time a mixed state), and 11 (44) weeks (median, 2 weeks) for spent ill with a mood episode was 31% (27%), and the euthymia. median was 23%. Initially, we examined time to recovery without re- PROBABILITY OF RECOVERY OVER TIME gard to mood episode type, ie, the different types of episodes were analyzed collectively. Table 2 displays the The association between the hypothesized predictors and proportion of subjects recovering from each of the first the probability of recovery from a mood episode was ana- 5 successive recurrent mood episodes. These first 5 epi- lyzed with a mixed-effects grouped-time survival model.

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Table 2. Time to Recovery From Successive Prospectively Observed Bipolar I Mood Episodesa

Mood Subjects With Elapsed Time From Onset of Mood Episode and Proportion of Subjects Who Recovered (95% CI)b,c Episode Mood Episode, No. No. 1mo 3mo 6mo 1y 2y 5y 1 219 0.150 (0.072-0.299) 0.470 (0.332-0.632) 0.670 (0.524-0.809) 0.790 (0.652-0.901) 0.890 (0.765-0.965) 0.950 (0.846-0.992) 2 181 0.150 (0.066-0.320) 0.480 (0.328-0.659) 0.630 (0.472-0.787) 0.760 (0.607-0.887) 0.850 (0.707-0.947) 0.900 (0.770-0.973) 3 146 0.180 (0.078-0.385) 0.450 (0.286-0.653) 0.650 (0.474-0.820) 0.770 (0.599-0.906) 0.870 (0.710-0.965) 0.950 (0.807-0.996) 4 120 0.260 (0.126-0.491) 0.590 (0.400-0.789) 0.700 (0.510-0.869) 0.780 (0.594-0.921) 0.870 (0.702-0.968) 0.910 (0.745-0.986) 5 102 0.120 (0.035-0.369) 0.410 (0.229-0.657) 0.710 (0.500-0.890) 0.900 (0.718-0.985) NAd NAd

Abbreviations: CI, confidence interval; NA, not applicable. a Recovery from a mood episode was defined according to Research Diagnostic Criteria,9 which require at least 8 consecutive weeks either with no symptoms of major depression, minor depression, mania, and hypomania or with only 1 or 2 symptoms of a mild degree and no impairment of psychosocial functioning. b Proportions were derived from Kaplan-Meier product-limit estimates. c Of 219 subjects with 1 prospectively observed mood episode, 79% (95% CI, 65%-90%) recovered within 1 year. Of 181 subjects with a second prospectively observed mood episode, 76% (95% CI, 61%-89%) recovered from that episode within 1 year. Of 146 subjects with a third prospectively observed mood episode, 77% (95% CI, 60%-91%) recovered from that episode within 1 year. Of 120 subjects with a fourth prospectively observed mood episode, 78% (95% CI, 59%-92%) recovered from that episode within 1 year. Of 102 subjects with a fifth prospectively observed mood episode, 90% (95% CI, 72%-99%) recovered from that episode within 1 year. d Estimates were not calculated because of limited numbers of subjects at risk for recovery.

1.0 First episode 0.9 Second episode Third episode 0.8 Fourth episode 0.7 Fifth episode

0.6

0.5

0.4

0.3

0.2 Proportion of Subjects in Episode 0.1

0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 Time From Onset of Mood Episode, wk

Figure. Time to recovery from the first 5 prospectively observed mood episodes. The survival curves depict the duration of the first 5 prospectively observed mood episodes and are based on cumulative recovery probabilities (Kaplan-Meier estimates). The 5 curves are similar, indicating that time to recovery in the sample as a whole was consistent across multiple mood episodes.

This analysis included 1178 of the 1208 prospectively ob- greater (HR=1.713; 95% CI, 1.373-2.137), and from hy- served mood episodes (98%) (the 2 mixed episodes and pomania was more than 4 times greater (HR=4.502; 95% 28 minor cycling episodes were not included because of CI, 3.466-5.849). Conversely, the probability of recov- small sample sizes). ery from an episode of major cycling was reduced by 56% Table 4 shows that the probability of recovery from relative to an episode of major depression (HR=0.438; a mood episode with severe onset (major depression or 95% CI, 0.351-0.548), and recovery from an episode of mania in week 1 of the episode, along with psychosis or mixed major cycling was reduced by 67% (HR=0.335; extreme impairment in functioning) was about 25% 95% CI, 0.251-0.446). smaller than that for an episode with less severe onset The mixed-effects model examined within-subject vari- (hazard ratio [HR]=0.746; 95% confidence interval [CI], ability in time to recovery from one mood episode to the 0.578-0.963). Cumulative morbidity (total number of next (without regard to mood episode type). The model years spent ill with any mood episode during prospec- yielded an intraclass correlation coefficient of 0.124, mean- tive follow-up) was also associated with a significantly ing that for each subject with 2 or more prospectively decreased probability of recovery, such that with each observed mood episodes, the duration of these multiple additional year of illness, the likelihood of recovery from episodes was inconsistent. the current mood episode was reduced by 8% (HR=0.917; 95% CI, 0.886-0.948). TREATMENT In addition, mood episode type was significantly associated with the probability of recovery. Compared with We examined the number of major depressive episodes an episode of major depression, the probability of recov- and manic episodes that were treated with somatic therapy ery from minor depression was 2 times greater for at least 4 consecutive weeks or, in the case of epi- (HR=2.027; 95% CI, 1.622-2.534), from mania was 71% sodes lasting less than 4 weeks, those that were treated

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Time Until Recovery (SE), wk Episodes, Mood Episode Type No. (%) First Quartileb Second Quartileb Third Quartileb Major depression 373 (31) 6.0 (0.6) 15.0 (1.1) 35.0 (3.7) Minor depression 157 (13) 3.0 (0.3) 7.0 (0.8) 15.0 (2.0) Mania 246 (20) 4.0 (0.3) 7.0 (0.7) 15.0 (2.0) Hypomania 126 (10) 2.0 (0.2) 3.0 (0.4) 6.0 (0.9) Major cycling 182 (15) 21.0 (1.4) 42.0 (4.2) 111.0 (23.5) Mixed major cycling 94 (8) 25.0 (4.6) 61.0 (19.9) 368.0 (104.7) Minor cycling 28 (2) 9.0 (1.4) 13.0 (4.9) 35.0 (20.7) Mixed 2 (Ͻ1) 7.0c 7.0c 76.0c Total 1208 (100)

a Consistent with Research Diagnostic Criteria,9 recovery from a mood episode was defined as at least 8 consecutive weeks either with no symptoms of major depression, minor depression, mania, and hypomania or with only 1 or 2 symptoms of a mild degree and no impairment of psychosocial functioning. b The first quartile indicates 25% of episodes; the second quartile, 50% of episodes; and the third quartile, 75% of episodes. As an example, there were 373 prospectively observed episodes of bipolar I major depression. Recovery from 25% of these episodes occurred within 6.0 (SE, 0.6) weeks of onset, recovery from 50% occurred within 15.0 (SE, 1.1) weeks, and recovery from 75% occurred within 35.0 (SE, 3.7) weeks. c The sample sizes are too small to estimate the SEs.

Table 4. Association Between Clinical Predictors and the Probability of Recovery From Bipolar I Mood Episodesa

Predictor Variable HR (95% CI) Z Score P Value No. of prior mood episodesb 1.005 (0.979-1.031) 0.351 .72 Severe onset of mood episodec 0.746 (0.578-0.963) −2.250 .02 Cumulative morbidityd 0.917 (0.886-0.948) −5.058 Ͻ.001 Mood episode typee Minor depression 2.027 (1.622-2.534) 6.205 Ͻ.001 Mania 1.713 (1.373-2.137) 4.767 Ͻ.001 Hypomania 4.502 (3.466-5.849) 11.270 Ͻ.001 Major cycling 0.438 (0.351-0.548) −7.250 Ͻ.001 Mixed major cycling 0.335 (0.251-0.446) −7.459 Ͻ.001

Abbreviations: CI, confidence interval; HR, hazard ratio. a Results are derived from mixed-effects grouped-time survival analysis. Each predictor except number of prior mood episodes was significantly associated with the probability of recovery. b Included only those episodes observed during prospective follow-up, beginning with the intake mood episode and ending with the mood episode immediately prior to the episode that was analyzed. c Defined such that in week 1 of the episode, the subject met the full criteria for major depression or mania, along with psychosis or extreme impairment in functioning. The probability of recovery from an episode with severe onset was 25% less than that for an episode with less severe onset. d Defined as the total number of years spent ill with any type of mood episode during prospective follow-up, beginning at study intake and ending at the week prior to onset of the mood episode that was analyzed. For each additional year that a subject had affective illness, the probability of recovery from the current episode was reduced by 8%. e The probability of recovery from each mood episode type was compared with the probability of recovery from an episode of major depression. Recovery from an episode of minor depression was 2 times more likely to occur than recovery from an episode of major depression, recovery from hypomania was 4.5 times more likely, and recovery from mania was 71% more likely. Recovery from an episode of major cycling was reduced by 56% relative to recovery from an episode of major depression, and recovery from mixed major cycling was reduced by 67%.

for the entire duration of the episode. For subjects with COMMENT a study intake diagnosis of (1) unipolar major depressive disorder, (2) schizoaffective disorder, major depression, or (3) bipolar II disorder, the treatment analyses The results describe the duration of bipolar I mood epi- did not include mood episodes that occurred prior to the sodes and factors significantly associated with the prob- first prospectively observed episode of mania. ability of recovery from a mood episode. During 326 episodes of major depression, 179 (55%) were treated with at least 1 mood stabilizer (aripipra- CLINICAL IMPLICATIONS zole, carbamazepine, clozapine, lamotrigine, lithium car- bonate, olanzapine, oxcarbazepine, quetiapine fuma- The mixed-effects model (Table 4) provided a number rate, risperidone, valproate sodium, or ziprasidone of clinically relevant results. First, the probability of re- hydrochloride), 111 (34%) were treated with at least 1 covery from a mood episode with severe onset was sig- mood stabilizer plus an antidepressant, and 89 (27%) were nificantly decreased compared with the probability of re- treated with an antidepressant in the absence of a mood covery from a mood episode with less severe onset. This stabilizer. During 246 manic episodes, 181 (74%) were finding raises the possibility that mood episodes with se- treated with at least 1 mood stabilizer. vere onset may be more difficult to treat. Future treat-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 ment studies or secondary analyses of archival random- however, the Stanley Foundation Bipolar Network found ized controlled trial data should examine whether severe that the mean number of manic recurrences actually ex- onset moderates recovery from mood episodes. ceeded the mean number of depressive recurrences,26 and The mixed-effects model and other survival analyses another group found that the number of manic and de- (Table 3) also demonstrated that there are clinically mean- pressive recurrences were approximately equal.37 In ad- ingful and statistically significant differences in the prob- dition, the 44% figure from our study is comparable to ability of recovery from different types of mood epi- the Zurich study,16 which found that depressive mood sodes. In particular, major cycling and mixed major cycling episodes composed 51% of the mood episodes observed episodes were much longer than other types of mood epi- in 26 years of follow-up. sodes, consistent with previous studies showing that cy- During prospective follow-up lasting up to 25 years, cling episodes are associated with poorer outcomes com- the mean number of mood episodes per subject in our pared with episodes of pure major depression or pure study was 5.5. In evaluating this number, it is worth not- mania.25 The observed prevalence and poorer prognosis ing certain aspects of the methods. First, the definition of cycling episodes help validate the concept of such epi- of recovery from a mood episode was relatively rigor- sodes. Thus, we encourage the work groups revising the ous: at least 8 consecutive weeks with 2 or fewer mood DSM-IV10 and the International Statistical Classification symptoms of a mild degree and no impairment in psy- of Diseases and Related Health Problems, 10th revision32 chosocial functioning. Second, alternating syndromes of to add cycling as a subtype for bipolar I mood episodes. depression and mood elevation separated by less than 8 The low intraclass correlation coefficient of 0.124 is consecutive weeks with euthymia were counted as a single consistent with many different clinical situations. For ex- cycling mood episode. In other studies, these alternat- ample, the intraclass correlation coefficient will be low ing syndromes are usually counted as separate mood if mood episode duration progressively decreases over episodes regardless of how little time, if any, elapses be- time or if mood episodes are initially shorter, then longer, tween the offset of one syndrome and the onset of the then shorter again. In addition, it will be low if mood epi- next (consistent with the DSM-IV10 and the Interna- sode duration progressively increases over time. The kin- tional Statistical Classification of Diseases and Related Health dling model, which predicts among other things that mood Problems, 10th revision32). The third issue is subject se- episode duration will increase from one episode to the lection. Some studies recruit patients from bipolar dis- next,33 is thus one of many competing explanations for order specialty clinics and may thus enroll subjects who the low intraclass correlation coefficient. This raises the are more resistant to maintenance treatment and there- possibility that there is a subgroup of subjects with kin- fore more vulnerable to recurrences. By contrast, the Col- dling that can be identified and clinically characterized. laborative Depression Study is strictly an observational study—treatment is not controlled by anyone associ- COURSE OF ILLNESS AND PREVIOUS STUDIES ated with the study and subjects are free to pursue treatment anywhere or to forego treatment. The Figure shows that the rate of recovery was fairly consistent across multiple episodes. Similar results were pre- LIMITATIONS viously obtained in a case-register study that used hos- pitalization as a proxy for mood episodes.34 One limitation is that there may be other types of mood Subjects were affectively ill for 31% of the follow-up episodes beyond the ones described in this article, eg, atypi- time. Previous analyses of Collaborative Depression Study cal depression. Another limitation is the absence of sub- subjects with bipolar I disorder found that they were af- jects with bipolar II disorder, who may be quite vulner- fectively ill for a mean of 47% of follow-up.35 The pri- able to mixed states. In addition, some subjects were mary reason for this discrepancy is that the 2 studies recruited closer to onset of the illness than others. Gener- handled subsyndromal symptoms differently. Subsyn- alizability is limited in that 89% of the subjects were inpa- dromal symptoms were defined as 1 or 2 symptoms of a tients at academic medical centers at study intake. Also, the mild degree and no impairment of psychosocial func- time that elapsed between assessments (initially 6 months tioning. The previous study35 counted a week with sub- and subsequently 12 months) may have introduced recall syndromal symptoms as a week in which the subject was bias and limited the accuracy of the results. affectively ill, whereas the present study did not (con- The diagnosis of hypomania required a minimal du- sistent with the procedures specified by Research Diag- ration of 1 week. This contrasts with the DSM-IV,10 in nostic Criteria9). which the minimal duration is 4 days. More so, there is At study intake, the mood state was mania for 65% of evidence that an adequate threshold is 2 days.38 Thus, our the subjects and mixed in another 7% (Table 1). This may study may have missed several episodes of hypomania. have yielded a sample that was predisposed to have fewer Another limitation is that treatment was not controlled depressive episodes during follow-up compared with the and may not have been optimal. For example, contrary to number of depressive episodes that occur in the general treatment guidelines,39,40 27% of the bipolar I major de- bipolar I population. Of the 1208 prospectively ob- pressive episodes were treated with an antidepressant in served mood episodes, 44% (Table 3) were depressive the absence of a mood stabilizer. However, this finding is (major or minor depression). This is considerably less very similar to what was observed in a nationally repre- than what was observed in the Systematic Treatment En- sentative sample of outpatients with bipolar disorder.41 hancement Program for Bipolar Disorder, which found Yet another limitation of this longitudinal study is at- that 72% of recurrences were depressive.36 In contrast, trition, which could have influenced some of the find-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 ings. However, mixed-effects models yield valid infer- ence, Eli Lilly, Forest Laboratories, Janssen, JDS, ences assuming ignorable attrition.42 Medtronic, Merck, Organon, Otsuka, Novartis, Pfizer, The mixed-effects model that examined clinical fac- Pharmacia, Pharmastar, Roche, Sepracor, Sierra Phar- tors associated with recovery from mood episodes did not maceuticals, Solvay, Vela Pharmaceuticals, and Wyeth- include chronic or episodic life stressors. New studies Ayerst; has received grants or research support from Eli seeking to further specify the factors associated with re- Lilly, Forest Laboratories, Organon, Pfizer, and Wyeth- covery should consider measuring such stressors. Ayerst; and has served on advisory boards for Abbott, Bristol-Myers Squibb, Cenerex, Cephalon, Cyberonics, CONCLUSIONS Cypress Bioscience, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Janssen, Merck, Mitsubishi Pharma, Neuronetics, Novartis, Organon, Pfizer, Sanofi- The median duration of bipolar I mood episodes was 13 Synthe´labo, Scirex, Sepracor, Somerset Pharmaceuti- weeks, and more than 75% of subjects recovered from their cals, Vela Pharmaceuticals, and Wyeth-Ayerst. episodes within 1 year of onset. Factors associated with a Funding/Support: This study was supported by grant significantly decreased probability of recovery from a mood MH25478-29A2 from the National Institute of Mental episode included severe onset of the mood episode, cy- Health. cling from one pole to the other (with no intervening pe- Role of the Sponsor: The National Institute of Mental riod of recovery), and greater cumulative morbidity. Fu- Health had no role in the design or conduct of this study; ture analyses will examine risk factors for recurrence of in the collection, management, analysis, and interpreta- bipolar I mood episodes and will use propensity score analy- tion of the data; and in the preparation, review, or ap- ses to study the effectiveness of treatment. proval of the manuscript. Additional Information: The manuscript was reviewed Submitted for Publication: January 16, 2009; final re- by the Publication Committee of the Collaborative De- vision received July 25, 2009; accepted July 29, 2009. pression Study and has its endorsement. The data for this Correspondence: David A. Solomon, MD, Mood Disor- article came from the National Institute of Mental Health ders Program, Department of Psychiatry, Rhode Island Collaborative Program on the Psychobiology of Depres- Hospital, 593 Eddy St, Providence, RI 02903-4970 sion–Clinical Studies. The Collaborative Program was ini- ([email protected]). tiated in 1975 to investigate nosologic, genetic, family, Author Contributions: All authors had full access to all prognostic, and psychosocial issues of mood disorders of the data in the study. Dr Solomon takes responsibil- and is an ongoing, long-term, multidisciplinary investi- ity for the integrity of the data and the accuracy of the gation of the course of mood and related affective disor- data analysis. ders. The original principal and coprincipal investiga- Financial Disclosure: Dr Solomon has served as an in- tors were from 5 academic centers and included Gerald vestigator for research funded by the National Institute Klerman, MD† (co-chairperson), Martin B. Keller, MD, of Mental Health, the National Institute of Neurological and Robert Shapiro, MD† (Massachusetts General Hos- Disorders and Stroke, Janssen, Merck, and Wyeth- pital, Harvard Medical School, Boston); Eli Robbins, MD,† Ayerst; as a consultant to Novartis, Shire, and Solvay Phar- Paula Clayton, MD, Theodore Reich, MD,† and Amos maceuticals; and on the lecture bureaus of AstraZeneca, Wellner, MD† (Washington University Medical School, GlaxoSmithKline, Pfizer, and Shire. Dr Leon has served St Louis, Missouri); Jean Endicott, PhD, and Robert as an investigator for research funded by the National In- Spitzer, MD (Columbia University, New York, New York); stitute of Mental Health and the National Institute on Drug Nancy Andreasen, MD, PhD, William Coryell, MD, and Abuse; is on data safety monitoring boards for Dainip- George Winokur, MD† (University of Iowa, Iowa City); pon Sumitomo Pharma America, Pfizer, Neuronetics, Or- and Jan Fawcett, MD, and William Scheftner, MD (Rush- ganon, and Vanda; and has recently served as a consul- Presbyterian-St Luke’s Medical Center, Chicago, Illi- tant to the US Food and Drug Administration, the National nois). The National Institute of Mental Health Clinical Institute of Mental Health, Avera, Best Practices, Ca- Research Branch was an active collaborator in the origin dence, Concordant Raters, Cortex Pharmaceuticals, Cy- and development of the Collaborative Program with Mar- beronics, Eli Lilly, MedAvante, and Noven. Dr Endicott tin M. Katz, PhD, branch chief, as the co-chairperson and has been an investigator for research funded by 4 of the Robert Hirschfeld, MD, as the program coordinator. Other National Institutes of Health and the New York State De- past collaborators include Jack Croughan, MD, M. Tra- partment of Mental Health; has received research sup- cie Shea, PhD, Robert D. Gibbons, PhD, Michael A. Young, port from Abbott, Bristol-Myers Squibb, Cyberonics, In- PhD, and David C. Clark, PhD. terneuron, Merck, Parke-Davis, Pfizer, Upjohn, and †Deceased. Wyeth-Ayerst; and has served as a consultant or advi- Additional Contributions: This study was conducted with sory board member for Abbott, AstraZeneca, Bayer the current participation of the following investigators: Schering, Berlex, Bristol-Myers Squibb, Cyberonics, Eli Martin B. Keller, MD (chairperson), Providence, Rhode Lilly, GlaxoSmithKline, Janssen, Novartis, Otsuka, Ova- Island; William H. Coryell, MD (co-chairperson), Iowa tion, Pfizer, Sanofi-Synthe´labo, and Wyeth-Ayerst. Dr City, Iowa; David A. Solomon, MD, Providence; Wil- Fiedorowicz has served as an investigator for research liam Scheftner, MD, Chicago, Illinois; Jean Endicott, PhD, funded by Eli Lilly. Dr Keller has received consulting fees Andrew C. Leon, PhD, and Joellen Loth, MSW, New York, or honoraria from Abbott, Bristol-Myers Squibb, Cen- New York; and John Rice, PhD, St Louis, Missouri. Other erex, Cephalon, Collegium, Cyberonics, Cypress Biosci- current contributors include Hagop S. Akiskal, MD, Jan

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