Research reportTime spent with symptoms in a cohort of bipolar disorder outpatients in Spain: A prospective, 18-month follow-up study
Introduction
Several follow-up studies of patients with bipolar disorder describe it as a chronic disorder with well-defined episodes, but in many cases with persistent affective symptoms of variable severity.
The National Institute of Mental Health-Collaborative Depression Study (CDS) (Coryell et al., 1989, Judd et al., 2005a, Judd et al., 2003a, Judd et al., 2003b, Judd et al., 2002) established that depressive and manic symptoms show a high degree of variability in patients and that they persist for a long time, both in type I and type II bipolar disorder patients. In that cohort, type I patients showed affective symptoms during approximately 47% of follow-up (mean, almost 13 years), while this proportion was somewhat greater, 54%, in type II patients. A predominance of depressive symptoms over (hypo) manic ones was reported (32% of follow-up time in type I and 50% in type II patients). Both groups had predominant sub-syndromal symptoms, including minor depression.
Joffe et al. (2004), followed 138 type I and II bipolar disorder patients during an average of 3 years. They found that only half of their patients remained euthymic. Patients spent 41% of the time with depressive symptoms, which were mainly sub-syndromal depressive, whereas they displayed hypomanic or manic symptoms only during 6% of the time.
In the Stanley Foundation research, patients suffered from depressive symptoms a mean of 33% of the time, three times as much as the time with manic symptoms (Post et al., 2003). In a one year follow-up, patients were euthymic 50% of the time (Kupka et al., 2007).
In Europe, Paykel et al. (2006) followed 253 patients during 18 months: they were asymptomatic 47% of the follow-up time, the rest of the time they endured minor or sub-syndromal symptoms, or were in definite episode.
In a post-hoc analysis, Frye et al. found that bipolar disorder I patients on maintenance therapy had sub-syndromal symptoms in 25% of follow-up visits during one year. Depressive sub-syndromal symptoms were more frequent, and were described in 20% of visits (Frye et al., 2006).
Most of these studies have been performed in Anglo-Saxon countries, most often with patients referred to tertiary care centers, which limits the generalizability of the results. Moreover, few studies have analyzed which clinical and socio-demographic variables are related with an increased or decreased risk of symptom persistence.
Our objective was to ascertain the time spent and the proportion of visits with affective symptoms during an 18-month follow-up in a representative cohort of outpatients attending secondary psychiatric care, as well as the variables related to those outcome measures.
Section snippets
Participants and data collection
Consecutive patients were recruited in outpatient clinics from two Mental Health Centers and a General Hospital belonging to three specific catchment areas in Madrid, Spain. Recruitment began in November 2004 until November 2008, and included new referrals as well as old cases. The three clinics care for bipolar disorder patients referred in every case from Primary Care, emergency rooms, and General Hospital patients. For their initial assessment, all patients (and a significant other, if
Primary end-points
Our main objectives were the assessment of time spent with an affective episode throughout the follow-up, and the assessment of the proportion of visits in episode or with sub-syndromal symptoms.
To avoid early drop-out bias, and to compare our results with previous research (Paykel et al., 2006, Bauer et al., 2009) only patients with at least twelve months of follow-up, until a maximum of 72 weeks, were included in this analysis.
Follow-up days in the different affective episode status categories
Results
296 bipolar patients were initially recruited. 168 (56.8%) were females and 128 (43.2%) males, with a mean age of 48.8 years. Mean duration of illness prior to inclusion was 18 years; and patients had a mean of 12.7 previous affective episodes. Of the 296 patients, 193 had a diagnosis of type I bipolar disorder (65.2%), 69 had type II BD (23.3%), 13 had schizoaffective disorder (4.4%), 6 had a diagnosis of cyclothymia (2%) and 6 of bipolar disorder not otherwise specified (5.1%). Further
Discussion
We assessed a cohort of bipolar disorder outpatients during 18 months, cared for in two Community Mental Health Centers and an outpatient psychiatric clinic of a General Hospital pertaining to three specific catchment areas in Madrid, Spain. At variance with previously published tertiary care series, our patients are referred by primary care physicians, emergency rooms, or General Hospital wards and outpatient clinics patients, and may be considered as representative of the population of
Sub-syndromal and minor symptoms
In the assessment of time in days with episode, minor depression and hypomanic episode were diagnosed according to DSM-IV-TR criteria (criteria A in the case of minor depression). Our method for collection of data may have hampered symptom identification. This could be particularly the case whenever hypomanic or mixed symptoms did not fulfill criteria for episode. Patients may have presented mild unnoticed symptoms of this type during a few days, which otherwise could have been detected on
Associated variables
We performed several analyses to assess the relationship between time in episode and proportion of visits in euthymia and non-euthymia and various socio-demographic and clinical parameters. We are fully conscious that associations cannot be considered causal. Corrections have been applied for multiple comparisons. We tried to limit the interrelated variables in regression analyses — for instance, EEAG score (axis V) has been excluded, since it comprises a clinical status assessment;
Variables related to the presence of sub-syndromal symptoms
In our study, better social adaptation was associated with a lower percentage of visits with sub-syndromal symptoms, whereas the presence of family history of psychiatric disorders increased this proportion. In the CDS cohort, where a predominance of sub-syndromal symptoms was observed, a positive family history of affective disorders predicted more time with symptoms (Judd et al., 2003a, Judd et al., 2002). We have been unable to find other research with this finding related to the presence of
Limitations
This study has several strengths and limitations. Strengths: The sample was more representative of the community than previous ones. The patients were repeatedly assessed in person by a psychiatrist during the 18-month follow-up. Each evaluation was performed by the same clinically experienced psychiatrist with a special interest in bipolar disorder and profound knowledge of the patients, in a naturalistic, public mental health setting. Moreover, the systematic psychometric assessment supports
Conclusions
In a Spanish bipolar outpatient cohort that was gathered to be representative of bipolar patients from the community, time with symptoms was shorter than previously found in tertiary care settings, but other outcomes were similar to selected samples. Our data confirm that patients with bipolar disorder spend considerable time of their course with depressive symptoms, both sub-syndromal and in episode, in a proportion which is surprisingly similar to samples from tertiary centers and severely
Role of funding source
This study was supported by AstraZeneca Pharmaceuticals only for statistical analysis. AstraZeneca did not have any role in the study design, in the collection, analysis and interpretation of data, in writing the report, nor in the decision to submit the paper for publication.
Conflict of interest
Dr. De Dios has received grants and served as consultant, advisor or speaker for the following entities: AstraZeneca, Bristol-Myers-Otsuka, Eli Lilly, Glaxo-Smith-Kline, Janssen-Cilag, Lundbeck, Pfizer, Sanofi-Aventis, Servier, Wyeth and Boëhringer-Ingelheim.
Dr. Ezquiaga has received grants and served as speaker for the following entities: AstraZeneca, Lundbeck, Sanofi-Aventis, and Boëhringer-Ingelheim.
Dr. García has received grants and served as speaker for the following entities: AstraZeneca,
Acknowledgment
We thank Dr. Jose Luis Agud, for his useful suggestions and contributions in the writing of this paper.
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Servicio de Psiquiatría, Hospital Universitario La Princesa, C/ Diego De León 62, 28006 Madrid, Spain. Tel.: + 34 91 520 22 00.
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Unidad de Trastornos Bipolares, Hospital Clínic, C/ Villarroel 170, 08036 Barcelona, Spain. Tel.: + 34 932275400.