The impact of the number of episodes on the outcome of Bipolar Disorder

S. Di Marzo, M.D.^*,**, A. Giordano,^*,***, I. Pacchiarotti, M.D. ^*,**, F. Colom, Psy.D., M.Sc., Ph.D.^*,****,
J. Sánchez-Moreno, Psy. D. ^*,*****, E.Vieta, M.D., Ph.D^*

^* Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona, Spain
^** Department of Psychiatry, Sant'Andrea Hospital, "La Sapienza" University, Rome, Italy
^*** Psychiatric Clinic III, Policlinico Umberto I, "La Sapienza" University, Rome, Italy
^**** Department of Psychological Medicine, Institute of Psychiatry, London
^***** Psychiatry Department, Universidad Autónoma de Madrid, Madrid, Spain
SPAIN, ITALY

Address for correspondence

ABSTRACT

BACKGROUND: Bipolar disorder is a highly recurrent severe psychiatric disorder. The number of episodes has been found consistently associated with poor outcome. It has been suggested that bipolar patients with long duration of illness and highly recurrent course show great impairment of global functioning.
OBJECTIVES The aim of this study is to assess the clinical course and outcome of patients with bipolar disorder I and II with a high number of mood episodes.
METHODS: We compared a group of bipolar I and II subjects whose number of episode was higher than ten (N = 167) with a similar-size representative sample of bipolar patients whose number of episodes was lower or equal than ten (N = 131).
RESULTS: Bipolar patients with more than 10 episodes have a more severe outcome of bipolar disorder. Qualification and occupational status was clearly worse for the highly recurrent group which showed a predominance of depressive polarity.
CONCLUSIONS: These data suggest that bipolar patients with a highly recurrent course have significant functional impairment. With the passing of time, bipolar illness tends to be ruled by depressive features. Treatment strategies may need to address this issue.

Key words: Recurrence, Bipolar disorder, Outcome.

Background

Bipolar illness is a lifelong psychiatric disorder which may carry severe impairment of patients' general functioning (Strakowski et al. 2000, Goldberg & Harrow 2004). In 1990, the World Health Organization studies reported that bipolar disorder is the sixth leading cause of worldwide disability (Lopez & Murrray 1998, World Health Organization 1999). Bipolar patients are "4 times more disabled than the general population" (Access Economics Report 2003); they have a variable course of illness and often do not experience complete recovery.

The course of bipolar disorder is typically episodic; the characteristic recurrence of the illness brings to personal and social costs that could also depend on the number of patient's episodes (Begley et al. 2001). Several studies have found high rates of recurrence in bipolar illness: it has been estimated that 50-90% of patients presents several bipolar episodes during the course of illness (Dion et al. 1988, Goodwin & Jamison 1990, Keck Jr. et al. 1995, Goldberg et al. 1995). The number of previous episodes has been found to be an important predictor of recurrence in bipolar disorder (Kessing et al. 2004). Poor occupational status after hospital discharge has been associated with the number of previous affective episodes (Tohen et al. 1990), and patients experience substantial impairment even in the absence of episodes (Gitlin et al. 1995). Moreover, the number of episodes may worsen the response to acute treatment in successive episodes (Swann et al. 2000).

Several investigations focused on the role of social and psychological risk factors in recurrence of bipolar disorder. For instance, bipolar patients were found prone to recurrence when socially disables. The clinical severity and the outcome of bipolar illness are generally associated to the number of episodes (Swann 2005): specifically, the number of episodes and the duration of illness have been found consistently associated with poorer outcome (Tohen et al. 1990, Goldberg et al. 1995).

Several studies have examined the outcome of bipolar disorder by using psychosocial variables. Data from 1450 patients showed that 30-60% of bipolar patients had detectable levels of psychosocial impairment (MacQueen et al. 2001). Long duration illness has been associated with impaired social functioning (Hajek et al. 2005).

In this study we compared a group of bipolar I and II patients with more than 10 episodes, with a group of bipolar I or II patients with a number of episodes equal or lower than 10. We hypothesized that the group of bipolar patients with more episodes would have a longer duration of illness, poorer outcome of bipolar disorder and worse social functioning.

Methods

All patients included in the present study were enrolled in the systematic follow up of the Bipolar Disorders Program of the Hospital Clinic and University of Barcelona which provides systematic and prospective collection of clinical, socio-demographic and treatment features of all patients included in the Bipolar Disorders Program. The Bipolar Disorders Program is a last-resort program providing care for difficult-to-treat bipolar patients derived from all over Spain but also provides clinical care to all bipolar patients coming from a specific catchment area Eixample Esquerre in Barcelona. In order to be included in our database, the patients gave written informed consent for the collection of data. This study was approved by the Ethical and Research Committee of the Hospital Clinic. All the patients fulfilling DSM-IV criteria for bipolar type I and II disorder were selected from the database to assess the outcome implications of their illness course. Hence, patients were divided according to the number of lifetime episodes: higher (group 1) or lower or equal than ten (group 2). We chose this cut-off according to several authors who found that the mean rating for severity and outcome of depression and mania was associated with a history of more than 10 prior episodes (Nolen et al. 2004). One hundred sixty-seven patients (N = 167, 56.04 %) fulfilled criteria for the highly recurrent group, whilst one hundred thirty-one (N = 131, 43.96 %) were considered to belong to the second group. Both groups were compared regarding several clinical and socio-demographic variables. All patients were retrospectively assessed by means of the Structured Clinical Interview for DSM-IV-axis I and II (SCID-I and SCID-II, respectively) (First et al. 1997a, First et al. 1997b), in order to detect all possible psychiatric comorbid diagnoses. Several clinical and socio-demographic variables were obtained from the structured interviews with the patient and their relatives: age, age of onset, age of first hospitalization, number of hospitalizations, the number of lifetime episodes, treatment compliance, history of psychosis and suicidal behaviour. Several more variables were specifically assessed: predominant polarity of episodes, seasonality according to DSM-IV criteria, rapid cycling (DSM-IV criteria as well), physical illness, psychiatric history of first-degree relatives, episode polarity at onset, occupational functioning and employment qualification.

Both groups were compared using several statistic techniques, including the chi-square statistic with Yates correction or Fisher exact test for the comparison of categorical data and Student t test was used for dimensional variables. All statistics were two-tailed and significance was set at p < 0.05.

Results

There were no significant differences between the two groups regarding bipolar subtype. Comparison of quantitative and qualitative variables is shown in Table I and II respectively. Regarding predominant polarity of episodes, mania or hypomania predominance was more prevalent amongst the less recurrent patients (30.9% vs. 14.8%), whilst depression was strongly associated to more than 10 episodes (33.3% vs. 18.6%) (p < 0.004). Depressive onset was more common amongst less recurrent patients (71.9% vs. 58%) (p < 0.02). Less recurrent patients had a higher number of psychotic symptoms in their first episodes (37%) compared to the highly recurrent group (26.1%) (p < 0.05). We found significant differences regarding seasonal pattern, which was more prevalent amongst the highly recurrent group (32.5% vs. 16.4%) (p < 0.003). Rapid cycling was obviously more prevalent in the highly recurrent group (24.5% vs. 10.7%) (p < 0.003). We did not find any significant difference between both groups regarding axis I and II comorbidity, but axis III comorbidity was more prevalent amongst highly recurrent patients (40% vs. 24%) (p < 0.005). There was no specific association between family history of psychiatric disorders or suicide and long duration of the bipolar disorder, whilst family history of affective disorders was more common in less recurrent patients (66.9% vs. 53.5%) (p < 0.003). Working for pay was more common amongst less recurrent group (64.9% vs. 48.5%) (p < 0.006). Regarding job qualification, we found a higher percentage of qualified patients in the less recurrent group (53.4% vs. 37.1%) (p < 0.006). As both groups differed in age, we performed an ANCOVA using age as a covariate, but differences remained significant anyway.

Discussion

The impairment of global functioning seems to be strongly associated with the higher number of episodes and long duration of bipolar disorder. The results of this study show that these patients have higher levels of functioning impairment when compared to bipolar patients with short-duration illness. Particularly, we found that bipolar patients with long duration of illness reported lower employment qualification and occupational status. This finding is congruent with previous studies reporting that the number of episodes had a negative impact on social functioning (Tohen et al. 1990, Goldberg et al. 1995, MacQueen et al. 2000, Hajek et al. 2005). It is possible that the high number of episodes may determine brain long-lasting biochemical changes that could have some consequences on global functioning in bipolar patients (Young et al. 1993, Post 1993). Moreover, some investigators have found that cognitive dysfunctions could worsen psychosocial outcome and employment in bipolar illness (Zarate, Jr. et al. 2000, MacQueen et al. 2001, Martinez-Aran et al. 2004a). Patients with multi-episode bipolar disorder would be more prone to have cognitive impairment (Martinez-Aran et al. 2004b), and this fact may be on the basis of poor social and occupational adjustment.

Regarding clinical data, the highly recurrent group presented depression as predominant polarity of bipolar illness. This finding is congruent with the results of other investigators (Judd et al. 2002, Judd et al. 2003). Some possible explanations of this result are that the lower percentage of manic episodes could reflect a pattern inherent in the course of illness, or that treatments utilized in bipolar disorder would be more effective for mania than for depression; on the other hand, it may be possible that functioning impairment may itself have a role on development of depressive relapses (MacQueen et al. 2000). It has been reported that depression is usually the first and most frequent type of episode during the course of bipolar illness (Perugi et al. 2000). On the other hand, depressive phases have been associated to a worse occupational and social functioning (Bauer et al. 2001, Calabrese et al. 2004). Depression appears to be associated with disability and comorbidity (Vieta et al. 2001, Chengappa et al. 2005), and depressive polarity seems to have a strong impact on global functioning (Furukawa et al. 2000). Our study seems to confirm this relationship. There are several possible explanations for the link between high rates of depressive episodes and impairment of functioning. Some authors suggest that bipolar patients may be more likely to perceive depressive phases as more weakening than manic episodes (Calabrese et al. 2004); other authors suggest that unresolved depressive symptoms may contribute to incomplete symptomatic recovery and lead to major dysfunction and disability (Chengappa et al. 2005). Another possible explication to this finding is that depressive episodes are often associated with cognitive dysfunctions that may worsen global functioning along the course of bipolar illness.

In our results, depressive onset was more common amongst LD-BD patients, possibly because patients with a depressive onset had higher overall morbidity during the follow-up period (Turvey et al. 1999). On the other hand, the link between rapid cycling and long duration of the illness has been previously described elsewhere (Kupka et al. 2005). Interestingly, rapid-cycling itself may partly explain the high levels of functional impairment (Dean et al. 2004).

In this study we found a highly prevalence of seasonal pattern in patients with recurrent course of bipolar disorder. In the clinical practice, this finding would suggest the importance of primary prevention programs that should focus on the prevention of seasonal recurrences in this subgroup of bipolar patients. This could be achieved by enhancing treatment strategies immediately before the critical period.

In our sample, DSM-IV Axis III comorbidity was more prevalent amongst the most recurrent patients; in agreement with previous studies (Fagiolini et al. 2002, Fagiolini et al. 2003), it is possible to consider this finding as another risk factor of poorer functioning outcome amongst the bipolar patients.

The primary limitation of this study is that informations regarding the number of episodes and the age at onset of bipolar disorder were assessed retrospectively. Although our study was based on all available sources of information, in the retrospective history it may exist more potential bias than in prospective data. Moreover, it was not possible to evaluate the episode duration and his impact on global functioning versus the impact of absolute number of episodes on outcome. The two groups also differed on their age, but this was obviously a correlate of longer duration of illness. When age was controlled for, the results remained the same, suggesting that differences were not related to age but truly related to the impact of the number of episodes.

Despite these potential limitations, our study highlights the association between the duration of bipolar illness and functioning outcome. Since episodes seem to beget further episode (Kessing et al. 2004), it may be important to develop strategies for early diagnosis and for prevention of relapses. In addition this study also suggests that bipolar patients with long duration of illness and higher number of episodes could benefit from rehabilitative intervention in order to minimize the functional impairment associated with bipolar illness. Moreover, our findings suggest that, with the passing of time, bipolar illness tends to be ruled by depressive features. Depressive polarity seems to have a strong impact on global functioning and such finding emphasizes the need to early recognize and treat depression in bipolar patients.

Acknowledgements

This work supported by an unrestricted grant of the Stanley Medical Research Institute (Bethesda, MD, USA)

References

Access Economics Report. Bipolar mood disorder: an anlysis of the burden of bipolar and related suicide in Australia. Melbourne: SANE Australia; 2003.         [ Links ]

Bauer MS, Kirk GF, Gavin C, Williford WO. Determinants of functional outcome and healthcare costs in bipolar disorder: a high-intensity follow-up study. J Affect Disord 2001; 65(3): 231-241.         [ Links ]

Begley CE, Annegers JF, Swann AC, Lewis C, Coan S, Schnapp WB, et al. The lifetime cost of bipolar disorder in the US: an estimate for new cases in 1998. Pharmacoeconomics 2001; 19(5 Pt 1): 483-495.         [ Links ]

Calabrese JR, Hirschfeld RM, Frye MA, Reed ML. Impact of depressive symptoms compared with manic symptoms in bipolar disorder: results of a U.S. community-based sample. J Clin Psychiatry 2004; 65(11): 1499-1504.         [ Links ]

Chengappa KN, Hennen J, Baldessarini RJ, Kupfer DJ, Yatham LN, Gershon S, et al. Recovery and functional outcomes following olanzapine treatment for bipolar I mania. Bipolar Disord 2005; 7(1): 68-76.         [ Links ]

Dean BB, Gerner D, Gerner RH. A systematic review evaluating health-related quality of life, work impairment, and healthcare costs and utilization in bipolar disorder. Curr Med Res Opin 2004; 20(2): 139-154.         [ Links ]

Dion GL, Tohen M, Anthony WA, Waternaux CS. Symptoms and functioning of patients with bipolar disorder six months after hospitalization. Hosp Community Psychiatry 1988; 39(6): 652-657.         [ Links ]

Fagiolini A, Frank E, Houck PR, Mallinger AG, Swartz HA, Buysse DJ, et al. Prevalence of obesity and weight change during treatment in patients with bipolar I disorder. J Clin Psychiatry 2002; 63(6): 528-533.         [ Links ]

Fagiolini A, Kupfer DJ, Houck PR, Novick DM, Frank E. Obesity as a correlate of outcome in patients with bipolar I disorder. Am J Psychiatry 2003; 160(1): 112-117.         [ Links ]

First MB, Spitzer R, Gibbon M. Structured Clinical interview for DSM-IV Axis I Disorders. Washington DC: American Psychiatric Press Inc; 1997a.         [ Links ]

First MB, Spitzer R, Gibbon M. Structured Clinical interview for DSM-IV Axis II Personality Disorders. Washington DC: American Psychiatric Press Inc; 1997b.         [ Links ]

Furukawa TA, Konno W, Morinobu S, Harai H, Kitamura T, Takahashi K. Course and outcome of depressive episodes: comparison between bipolar, unipolar and subthreshold depression. Psychiatry Res 2000; 96(3): 211-220.         [ Links ]

Gitlin MJ, Swendsen J, Heller TL, Hammen C. Relapse and impairment in bipolar disorder. Am J Psychiatry 1995; 152(11): 1635-1640.         [ Links ]

Goldberg JF, Harrow M. Consistency of remission and outcome in bipolar and unipolar mood disorders: a 10-year prospective follow-up. J Affect Disord 2004; 81(2): 123-131.         [ Links ]

Goldberg JF, Harrow M, Grossman LS. Course and outcome in bipolar affective disorder: a longitudinal follow-up study. Am J Psychiatry 1995; 152(3): 379-384.         [ Links ]

Goodwin FK, Jamison KR. Manic-Depressive Illness. New York: Oxford University Press; 1990.         [ Links ]

Hajek T, Slaney C, Garnham J, Ruzickova M, Passmore M, Alda M. Clinical correlates of current level of functioning in primary care-treated bipolar patients. Bipolar Disord 2005; 7(3): 286-291.         [ Links ]

Judd LL, Akiskal HS, Schettler PJ, Coryell W, Endicott J, Maser JD, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003; 60(3): 261-269.         [ Links ]

Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002; 59(6): 530-537.         [ Links ]

Keck PE, McElroy SL, Strakowski SM, West SA, Hawkins JM, Huber TJ, et al. Outcome and comorbidity in first- compared with multiple-episode mania. J Nerv Ment Dis 1995; 183(5): 320-324.         [ Links ]

Kessing LV, Hansen MG, Andersen PK, Angst J. The predictive effect of episodes on the risk of recurrence in depressive and bipolar disorders: a life-long perspective. Acta Psychiatr Scand 2004; 109(5): 339-344.         [ Links ]

Kupka RW, Luckenbaugh DA, Post RM, Suppes T, Altshuler LL, Keck PE, et al. Comparison of rapid-cycling and non-rapid-cycling bipolar disorder based on prospective mood ratings in 539 outpatients. Am J Psychiatry 2005; 162(7): 1273-1280.         [ Links ]

Lopez AD, Murrray CC. The global burden of disease, 1990-2020. Nat Med 1998; 4(11): 1241-1243.         [ Links ]

MacQueen GM, Young LT, Joffe RT. A review of psychosocial outcome in patients with bipolar disorder. Acta Psychiatr Scand 2001; 103(3): 163-170.         [ Links ]

MacQueen GM, Young LT, Robb JC, Marriott M, Cooke RG, Joffe RT. Effect of number of episodes on wellbeing and functioning of patients with bipolar disorder. Acta Psychiatr Scand 2000; 101(5): 374-381.         [ Links ]

Martinez-Aran A, Vieta E, Colom F, Torrent C, Sanchez-Moreno J, Reinares M, et al. Cognitive impairment in euthymic bipolar patients: implications for clinical and functional outcome. Bipolar Disord 2004a; 6(3): 224-232.         [ Links ]

Martinez-Aran A, Vieta E, Reinares M, Colom F, Torrent C, Sanchez-Moreno J, et al. Cognitive function across manic or hypomanic, depressed, and euthymic states in bipolar disorder. Am J Psychiatry 2004b; 161(2): 262-270.         [ Links ]

Nolen WA, Luckenbaugh DA, Altshuler LL, Suppes T, McElroy SL, Frye MA, et al. Correlates of 1-year prospective outcome in bipolar disorder: results from the Stanley Foundation Bipolar Network. Am J Psychiatry 2004; 161(8): 1447-1454.         [ Links ]

Perugi G, Micheli C, Akiskal HS, Madaro D, Socci C, Quilici C, et al. Polarity of the first episode, clinical characteristics, and course of manic depressive illness: a systematic retrospective investigation of 320 bipolar I patients. Compr Psychiatry 2000; 41(1): 13-18.         [ Links ]

Post RM. Malignant transformation of affective illness: prevention and treatment. Direct Psychiatry 1993; 13: 1-11.         [ Links ]

Strakowski SM, Williams JR, Fleck DE, Delbello MP. Eight-month functional outcome from mania following a first psychiatric hospitalization. J Psychiatr Res 2000; 34(3): 193-200.         [ Links ]

Swann AC. Long-term treatment in bipolar disorder. J Clin Psychiatry 2005; 66 (Suppl 1): s7-s12.         [ Links ]

Swann AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD. Mania: differential effects of previous depressive and manic episodes on response to treatment. Acta Psychiatr Scand 2000; 101(6): 444-451.         [ Links ]

Tohen M, Waternaux CM, Tsuang MT. Outcome in Mania. A 4-year prospective follow-up of 75 patients utilizing survival analysis. Arch Gen Psychiatry 1990; 47(12): 1106-1111.         [ Links ]

Turvey CL, Coryell WH, Arndt S, Solomon DA, Leon AC, Endicott J, et al. Polarity sequence, depression, and chronicity in bipolar I disorder. J Nerv Ment Dis 1999; 187(3): 181-187.         [ Links ]

Vieta E, Colom F, Corbella B, Martinez-Aran A, Reinares M, Benabarre A, et al. Clinical correlates of psychiatric comorbidity in bipolar I patients. Bipolar Disord 2001; 3(5): 253-258.         [ Links ]

World Health Organization. The world health report. Geneva: World Health Organization; 1999.         [ Links ]

Young LT, Li PP, Kish SJ, Siu KP, Kamble A, Hornykiewicz O, et al. Cerebral cortex Gs alpha protein levels and forskolin-stimulated cyclic AMP formation are increased in bipolar affective disorder. J Neurochem 1993; 61(3): 890-898.         [ Links ]

Zarate CA, Tohen M, Land M, Cavanagh S. Functional impairment and cognition in bipolar disorder. Psychiatr Q 2000; 71(4): 309-329.         [ Links ]

Address for correspondence:
E Vieta
Institute of Neurosciences, Hospital Clinic
Villarroel 170, 08036 Barcelona, Spain
Ph: +34-93-2275401
Fax: +34-93-2275477
e-mail: evieta@clinic.ub.es
SPAIN