Time spent with symptoms in a cohort of bipolar disorder outpatients in Spain: A prospective, 18-month follow-up study

Journal of Affective Disorders xxx (2009) xxx–xxx

JAD-04448; No of Pages 8

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Research report

Time spent with symptoms in a cohort of bipolar disorder outpatients inSpain: A prospective, 18-month follow-up study

Consuelo De Dios a,b,⁎, Elena Ezquiaga b,c,1, Aurelio Garcia d,2, Begoña Soler e,3, Eduard Vieta f,4

a University Hospital La Paz, Madrid, Spainb Autónoma University, Madrid, Spainc University Hospital La Princesa, Madrid, Spaind Mental Health Center San Blas, Madrid, Spaine EC-Bio, Madrid, Spainf Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain

a r t i c l e i n f o

⁎ Corresponding author. Servicio de Psiquiatría, HoPaz, Paseo de la Castellana 264, 28046 Madrid, Spain.

E-mail addresses: [email protected] ([email protected] (E. Ezquiaga), [email protected]@ecbio.net (B. Soler), [email protected] (E. Vie

1 Servicio de Psiquiatría, Hospital Universitario LaLeón 62, 28006 Madrid, Spain. Tel.: +34 91 520 22 00

2 C/ Julia García Boutan, 8, 28022 Madrid, Spain. Te3 C/ Rosa de Lima, 1, Edificio ALBA, Oficina 016, 2823

Spain. Tel.: +34 916300480; fax: +34 916303668.4 Unidad de Trastornos Bipolares, Hospital Clínic, C/

Barcelona, Spain. Tel.: +34 932275400.

0165-0327/$ – see front matter © 2009 Elsevier B.V.doi:10.1016/j.jad.2009.12.006

Please cite this article as: De Dios, C., et alprospective, 18-month follow-up study, J

a b s t r a c t

Article history:Received 14 November 2009Received in revised form 4 December 2009Accepted 6 December 2009Available online xxxx

Objective: Most research on the symptomatic burden in bipolar disorder has included patientsenrolled exclusively from tertiary centers, and only a few studies have analyzed factors relatedto it. We investigated the proportion of time and the proportion of visits with symptoms in acohort of bipolar outpatients followed-up for 18 months, as well as the associated variables.Methods: 296 DSM-IV-TR bipolar outpatients were included in a naturalistic longitudinalfollow-up study, with quarterly assessment. Euthymia was defined by a Hamilton DepressionRating Scale score b7 and Young Mania Rating Scale score b5. Depressive episode, by a HDRSscore of N17, hypomanic episode by a YMRS score of 10–20, andmanic episode by a YMRS scoreN20. Sub-syndromal symptoms required scores of 7–17 in HDRS and 5–10 in YMRS. Based on adetailed recall of affective symptoms in the time between interviews, time in episode was alsodetermined.Results: Patients were symptomatic for one third of the follow-up, and also one third of the visits.They spent three times more days depressed than manic or hypomanic. More prior affectiveepisodes were related both to more time symptomatic and more visits with symptoms.Limitations: Some of the data were collected retrospectively. Treatment was naturalistic.Conclusions: In a bipolar outpatient cohort from Spain, time with symptoms was shorter thanpreviously found in tertiary care settings. In accordance with other longitudinal studies, thosepatients spent much more time depressed than manic.

© 2009 Elsevier B.V. All rights reserved.

Keywords:Bipolar disordersDisorder, bipolarSymptoms, affectiveSub-syndromal symptomsTime with symptomsDepression, bipolar

spital Universitario LaTel.: +34 727 72 76.. De Dios),(A. Garcia),ta).Princesa, C/ Diego De.l.: +34 91 313 55.0, LAS ROZAS, Madrid,

Villarroel 170, 08036

All rights reserved.

., Time spent with symp. Affect. Disord. (2009),

1. Introduction

Several follow-up studies of patients with bipolar disorderdescribe it as a chronic disorder with well-defined episodes,but in many cases with persistent affective symptoms ofvariable severity.

The National Institute of Mental Health-CollaborativeDepression Study (CDS) (Coryell et al., 1989; Judd et al.,2005a, 2003a,b, 2002) established that depressive and manicsymptoms show a high degree of variability in patients andthat they persist for a long time, both in type I and type IIbipolar disorder patients. In that cohort, type I patients

toms in a cohort of bipolar disorder outpatients in Spain: Adoi:10.1016/j.jad.2009.12.006

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showed affective symptoms during approximately 47% offollow-up (mean, almost 13 years), while this proportion wassomewhat greater, 54%, in type II patients. A predominance ofdepressive 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 bipolardisorder patients during an average of 3 years. They foundthat only half of their patients remained euthymic. Patientsspent 41% of the timewith depressive symptoms, which weremainly sub-syndromal depressive, whereas they displayedhypomanic or manic symptoms only during 6% of the time.

In the Stanley Foundation research, patients suffered fromdepressive symptoms a mean of 33% of the time, three timesas much as the time with manic symptoms (Post et al., 2003).In a one year follow-up, patients were euthymic 50% of thetime (Kupka et al., 2007).

In Europe, Paykel et al. (2006) followed 253 patientsduring 18 months: they were asymptomatic 47% of thefollow-up time, the rest of the time they endured minor orsub-syndromal symptoms, or were in definite episode.

In a post-hoc analysis, Frye et al. found that bipolar disorderI patients on maintenance therapy had sub-syndromal symp-toms in 25% of follow-up visits during one year. Depressivesub-syndromal symptoms were more frequent, and weredescribed 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 tertiarycare centers, which limits the generalizability of the results.Moreover, few studies have analyzed which clinical andsocio-demographic variables are related with an increased ordecreased risk of symptom persistence.

Our objective was to ascertain the time spent and theproportion of visits with affective symptoms during an 18-month follow-up in a representative cohort of outpatientsattending secondary psychiatric care, as well as the variablesrelated to those outcome measures.

2. Methods

2.1. Participants and data collection

Consecutive patients were recruited in outpatient clinicsfrom two Mental Health Centers and a General Hospitalbelonging to three specific catchment areas in Madrid, Spain.Recruitment began in November 2004 until November 2008,and included new referrals aswell as old cases. The three clinicscare for bipolar disorder patients referred in every case fromPrimary Care, emergency rooms, and General Hospital patients.For their initial assessment, all patients (and a significant other,if possible) underwent a structured interview where bipolardisorder was diagnosed according to DSM-IV-TR criteria usingthe MINI (Mini International Neuropsychiatric Interview)(Sheehan et al., 1998). Several clinical variables were assessed,such as number and polarity of previous lifetime episodes,number and polarity of previous last-year episodes, hospitali-zations, age of onset, polarity of first episode, history of rapidcycling and seasonal pattern according to DSM-IV-TR criteria,history of psychotic symptoms during affective episodes,suicidal behavior, psychosocial stress (axis IV DSM-IV-TR),

Please cite this article as: De Dios, C., et al., Time spent with sympprospective, 18-month follow-up study, J. Affect. Disord. (2009),

andmedical andpsychiatric comorbidities, aswell as other datasuch as psychiatric morbidity in first degree family members,socio-demographic variables, and predominant polarity asdefined by Colom et al. (2006). At baseline, the 21-itemHamilton Depression Rating Scale (HAMD), the Young ManiaRating Scale (YMRS) and the Clinical Global Impression scalemodified for bipolar disorder (CGI-BP-M) (Vieta Pascual et al.,2002) were measured. Follow-up included clinical and psy-chometric assessments every three months. Episodes weredefined according to DSM-IV-TR criteria; severity of symptomswas rated by means of HAMD, YMRS, and CGI-BP. For thediagnosis of minor depressive episodes, we used criterion A ofthe DSM-IV-TR research criteria for minor depressive disorder.Social functioning was evaluated according to the SocialAdaptation Self-Evaluation Scale (SASS) (Bosc et al., 1997) inits Spanish validated version (Bobes et al., 1999). This scalewasapplied while the patient fulfilled clinical criteria of euthymia.

For the present study, inclusion criteria were:

(a) Age 18 years or more(b) History of bipolar disorder (type I, II, cyclothymia,

bipolar disorder not otherwise specified, and schizoaf-fective disorder, bipolar type) meeting DSM-IV-TRcriteria, and validated with the MINI interview.

Exclusion criteria were:

(a) Mental retardation, brain damage or severe cognitivedeficit.

(b) Pregnancy.

The study received approval by the Ethics Committee ofthe Hospital Universitario La Paz (Madrid) (PI-521) and thepatients provided informed consent.

The same general psychiatrist evaluated the patients ateach visit and during the whole study, including baselineassessment. All patients were followed for 18 months(518 days) if possible, with quarterly assessments includingpsychometric and clinical evaluation of affective status. Sinceit was a naturalistic study, intermediate visits were alsoperformed, according to standard clinical practice, if needed.

In each visit an estimation of the time (days) that thepatient had spent in episode, as well as the number of days ineuthymia since the last visit, was performed.Major andminordepressive, hypomanic, manic and mixed episodes wereconsidered. If the patient had not recovered from the lastrecorded affective episode, this was not counted for thenumber of episodes, but the days with symptoms were takeninto account. The patient was considered recovered betweentwo visits if he had been asymptomatic or with minimalsymptoms during at least 8 weeks.

Switching counted as a new episode.For the estimation of time (days) in episode we used

information provided by the patient, the clinician's assess-ment, and, whenever possible, the evaluation by family,significant others, or other sources of information. In everycase, clinical records (emergency room reports, notes inclinical record, hospital discharge reports) were searched into complete the information as much as possible.

In the quarterly psychometric evaluations, patient symp-toms in the previous week were evaluated with the scalesHamilton Depression Rating Scale—21 items (HDRS) andYoung Mania Rating Scale (YMRS); the Clinical Global

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Impression through the CGI-BP-M was also considered. Cut-off points for HAMD and YMRS scores were establishedbeforehand by consensus, using the literature recommenda-tions (Berk et al., 2007; Frye et al., 2006; Gopal et al., 2005;Tohen et al., 2005, 2006; Yatham et al., 2004). Euthymia atvisits was defined as a HDRS-21 score b7 and a YMRS scoreb5, in the absence of hospital admission. A depressive episodewas defined by a HDRS score of N17, hypomanic episode by aYMRS score of 10–20, and a manic episode by a YMRS scoreN20. Sub-syndromal symptoms required scores of 7–17 inHDRS (depressive sub-syndromal symptoms) or 5–10 inYMRS (hypomanic sub-syndromal symptoms).

Inter-rater reliability using Cohen's kappa index, calculat-ed by the statistical program SPSS 12.0, was 0.826 (95%CI=0.460–0.986) for Hamilton Depression Scale and 0.874(95% CI=0.552–0.990) for Young Mania Scale. Global Kappaindex (Epidat 3.1 statistical package (PAHO, 2006)) for CGIscales has been 0.69 for CGI-General, 0.66 for CGI-Depressionand 0.803 for CGI-Mania.

The treating psychiatrist chose the therapy according tocurrent treatment guidelines. Treatment included mood stabi-lizers (lithium, valproate, carbamazepine, oxcarbamazepine,lamotrigine, topiramate andgabapentine), classical andatypicalantipsychotics, antidepressants and benzodiacepines, as wellas other treatments (i.e., tiroxine, biperiden) if needed. Nostructured psychotherapy was systematically applied.

3. Data analysis

3.1. Primary end-points

Our main objectives were the assessment of time spentwith an affective episode throughout the follow-up, and theassessment of the proportion of visits in episode or with sub-syndromal symptoms.

To avoid early drop-out bias, and to compare our resultswith previous research (Paykel et al., 2006; Bauer et al., 2009)only patients with at least twelve months of follow-up, until amaximum of 72 weeks, were included in this analysis.

Follow-up days in the different affective episode statuscategories were computed for each patient as the percentageof the total number of follow-up days. To analyze the pro-portion of time patients spent in affective episodes related tofollow-up time, we considered the ratio between the numberof days in episode (major and minor depression, hypomanicand manic) and the number of days of follow-up (“time indays in episode or in euthymia”).

For the assessment of the proportion of visits in euthymiaor in the different pre-specified diagnostic categories, weconsidered the ratio between the number of visits in episode(major and minor depressive, hypomanic and manic) orwith sub-syndromal symptoms – according to psychometriccriteria – and the number of visits of follow-up. Weperformed an intention to treat analysis up to the maximumfollow-up for each patient, i.e., intention to treat was notcarried forward to times longer than real follow-up.

3.2. Secondary end-points

We performed univariate and multivariate analyses of therelationshipbetween theproportionof days in episodeaswell as

Please cite this article as: De Dios, C., et al., Time spent with sympprospective, 18-month follow-up study, J. Affect. Disord. (2009),

the proportion of visits in the various affective states (euthymiavs. non-euthymia, euthymia vs. sub-syndromal symptoms) andclinical and socio-demographic variables. Following procedureshave been used: For univariate analysis, χ2 analyses ofcategorical variables; Student's t test for independent variablesto compare quantitative data; and ANOVA for one factor appliedto variables with more than two categories. In the analyses ofevolution of quantitative variables during follow-up, a generallinear model ANOVA for repeated measurements was used. Ineach case, correction for multiple comparisons (Bonferroni orGames Howell) has been applied.

In multivariate analysis, we performed logistic regressionfor the study of the relation of primary outcome measureswith the presence of socio-demographic, clinical and coursevariables considered potential prognostic variables, basedupon previous literature and clinical relevance. Variablesincluded in regression equations are highlighted in Table 1.

4. Results

296 bipolar patients were initially recruited. 168 (56.8%)were females and 128 (43.2%) males, with a mean age of48.8 years. Mean duration of illness prior to inclusion was18 years; and patients had a mean of 12.7 previous affectiveepisodes. Of the 296 patients, 193 had a diagnosis of type Ibipolar disorder (65.2%), 69 had type II BD (23.3%), 13 hadschizoaffective disorder (4.4%), 6 had a diagnosis of cyclo-thymia (2%) and 6 of bipolar disorder not otherwise specified(5.1%). Further demographic and clinical details are providedin Table 1.

Psychotropic treatment at baseline is shown in Fig. 1.Mean number of drugs per patient was 2.6 (CI95%=2.4–2.8).

213 patients had a minimum follow-up of 12 months, anda maximum of 18 months (518 days) and these wereincluded in the main analyses. There were no relevantdifferences in socio-demographic variables between thesepatients and the 83 patients eliminated because of shortertime of follow-up. At baseline, using psychometric criteria,50.2% of patients were symptomatic: 32.7% had sub-syndro-mal symptoms, and 17.5% suffered a depressive, hypomanic,manic or mixed episode. One third of patients had depressivesymptoms at baseline, either sub-syndromal or fulfillingepisode criteria.

4.1. Primary end-points

The analysis of days in episode revealed that patientsfulfilled criteria of affective episode at 34.5% of the follow-uptime (95% CI=29.6–39.5) (Table 2). Of the total follow-uptime, 24% was spent in depressive episode (Table 2), whichamounted to two thirds of the total symptomatic time, asshown in Fig. 2.

As to the percentage of visits in euthymia or non-euthymia (sub-syndromal symptoms or episode) during72 weeks of follow-up, mean weighted percentages perpatient are shown in Table 3. Patients were found in non-euthymia in approximately one third of the visits (36.6%; 95%CI 33.1–40). The proportion of visits in episode is similarto the proportion of visits with any type of sub-syndromalsymptoms, again with an overwhelming predominance ofdepressive symptoms. Sixteen percent of patients remained

toms in a cohort of bipolar disorder outpatients in Spain: Adoi:10.1016/j.jad.2009.12.006

Table 1Socio-demographic and clinical characteristics at intake.

Female 168 (56.8%)Age (mean, 95% CI) 48.1 (47.2–50.4)Marital status

Married 123 (41.6%)Separated/divorced/widowed 54 (18.2%)Never married 119 (40.2%)

Household compositionAlone 56 (19%)With family 223 (75.6%)Other 16 (5.4%)

EducationHigh school or less 178 (60.1%)College or more 118 (39.9%)

Job skillsUnqualified worker 135 (46.4%)Qualified worker 156 (53.5%)

EmploymentWorking 125 (42.4%)Other 170 (57.6%)

Axis III diagnosis 140 (47.3%)Axis I diagnosis

Bipolar disorder I 193 (65.2%)Bipolar disorder II 69 (23.3%)Bipolar disorder NOS 15 (5.1%)Cyclothymia 6 (2%)Schizoaffective disorder 13 (4.4%)

Axis II diagnosis 69 (24%)Axis IV diagnosis 105 (37.2%)Previous psychosis 158 (53.9%)Currently psychotic 9 (3%)Rapid cycling 9 (3%)Seasonal pattern 39 (13.6%)Suicide thoughts 17 (5.8%)Alcohol abuse or dependence 26 (8.9%)Drug abuse or dependence 21 (7.2%)Treatment adherence 73.5% good, 21.6% fair,

4.8% badBipolar disorder duration (y)(mean, range)

18 (0.1–57)

Lifetime affective episodes(mean, range)

12.7 (1–61)

Patients with episodes last year 221 (74.7%)Family psychiatric history 166 (56.8%)Initial polarity 23% manic; 65% depressive;

2% mixed/unknownTime until MS (months)(mean, CI95%)

125.4 (112.3–138.5)

Previous hospitalizations 201 (69%)Suicide attempts 79 (24%)SASS (mean, SD) 39 (7.9)Patients with axis I comorbidity 94 (31.8%)Predominant polarity

Depressive 22%Manic 24%

Abbreviations: MS, mood stabilizers; NOS, not otherwise specified; SASSsocial adaptation self-evaluation scale.

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Please cite this article as: De Dios, C., et al., Time spent withprospective, 18-month follow-up study, J. Affect. Disord. (

,

euthymic in every visit, up to 72 weeks. The types ofsymptoms in the visits are shown in Fig. 3.

4.2. Secondary end-points

Regarding prognostic factors, an increased time in affectiveepisode was related to the presence of suicidal ideation atbaseline (p=0.001; B=49.83, 95% CI=21.32–78.34), moreaffective episodes in the year prior to the inclusion (p=0.014,

symp2009),

B=8.36, 95% CI=1.73–14.98), and psychosocial stress atbaseline (p=0.032, B=3, 95% CI=026–5.9).

As to the proportion of visits, we found an increased risk ofsuffering of any type of affective symptoms (episode or sub-syndromal) in follow-up visits in patients withmore previousmood episodes, both in the year prior to inclusion (p=0.004;B=6.17, 95% CI=2–10.3), and earlier (p=0.021; B=0.59,95% CI=0.09–1.10). A seasonal pattern was associated withlower risk (p=0.008; B=−16.0, 95% CI=−27.88, −4.29).

Variables specifically related to the risk of sub-syndromalsymptoms during follow-upwere family history of psychiatricdisease and social adaptation in the SASS scale. Positive familyhistory of psychiatric disease increased the risk in our study(p=0.042, B=8.55, 95% CI=0.32–16.77), whereas bettersocial adaptation at baseline was associated with less risk ofsub-syndromal symptoms (p=0.020, B=−0.77, 95% CI=−1.42, −0.12).

In our data, neither time with affective symptoms in days,nor the proportion of visits with affective symptoms, wererelated to other variables such as gender, age, social factorsother than psychosocial stress, type of bipolar disorder, initialpolarity, predominant polarity, psychiatric or medical comor-bidity, or duration of the disease.

5. Discussion

We assessed a cohort of bipolar disorder outpatients during18 months, cared for in two Community Mental Health Centersand an outpatient psychiatric clinic of a General Hospital per-taining to three specific catchment areas in Madrid, Spain. Atvariance with previously published tertiary care series, ourpatients are referred by primary care physicians, emergencyrooms, or General Hospital wards and outpatient clinics pa-tients, and may be considered as representative of the pop-ulation of patientswith bipolardisorder seeking for clinical care.

According to pre-specified clinical and psychometriccriteria, around 50% of patients had affective symptoms atinclusion. This proportion was sustained, with minimalvariation, throughout 18 months of prospective follow-up.

Our main objectives were the assessment of illness-related morbidity by means of the time that the patientsspent in episode throughout the follow-up, and the propor-tion of visits in various affective states. We found patientswere in episode one third of the time, and they weresymptomatic (in episode or with sub-syndromal symptoms)in one third of visits throughout the 72-week follow-up.

Although we have some resemblances with previousresearch (i.e., the predominance of female patients), com-paring our results with those of other cohorts becomesdifficult because of certain differences. Our cohort comprisesa considerable proportion of bipolar II subjects (23%), inaccordance with some of the previous research (Judd et al.,2003b), but greater than the majority of published cohorts(Joffe et al., 2004; Kupka et al., 2007; Paykel et al., 2006).

Another relevant difference concerns the setting in whichwe recruited patients, that are not tertiary care centers— as isthe case in several previous studies. Methods and criteria forthe assessment and definition of affective states are alsodissimilar. Research on CDS cohort is widely cited (Judd et al.,2003a,b, 2005b, 2002). The main difference with our work isfollow-up time. CDS excluded patients with less than two

toms in a cohort of bipolar disorder outpatients in Spain: Adoi:10.1016/j.jad.2009.12.006

Fig. 1. Treatment at baseline (% of patients).

Table 2Proportion of time (in days) in episode.

Affective episode % 95% CI

Major depression 11.8 8.7–14.9Mania 1.6 0.8–2.3Hypomania 6.7 4.5–8.9Mixed 2.6 1.4–3.8Minor depression 11.9 8.5–15.2Total time in episode 34.5 29.6–39.5

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years of follow-up and mean follow-up time was 12 years.Disease onset in almost 50% of patients of this cohort wasbefore 20 years of age, and all patients were in acute episodeat inclusion, which may have biased the sample in terms ofseverity. As reported by Paykel, patients in episode atinclusion spend more time with symptoms (Paykel et al.,2006). The only study that, as this one, recruited patients in

Fig. 2. Time with affective episodes (in days).

Please cite this article as: De Dios, C., et al., Time spent with sympprospective, 18-month follow-up study, J. Affect. Disord. (2009),

Community Mental Health Centers, was one conducted in UK(Paykel et al., 2006).

Lastly, another important difference in our work resides inthe way we have evaluated sub-syndromal symptoms,defined by psychometric criteria in quarterly evaluationsconsidering the previous week. This could also explain someof the differences with previous research.

As previously discussed, these reports found that patientssuffer from affective symptoms approximately during half ofthe time of follow-up. We believe that differences in baselinecharacteristics, as well as dissimilar data collection andassessment at follow-up may explain the differences regard-ing time in euthymia along the course. Probably, patientsfrom a tertiary care setting have more severe disease thanthose cared for in General Psychiatric Mental Health clinics. Inanother recent naturalistic study, in which time withsymptoms was a secondary endpoint, the researchers foundthat patients reported being euthymic 70% of the time. Thisstudy used daily self-recording of mood status (Bauer et al.,2009).

Nevertheless, despite the shorter time with symptomsrecorded in our patients, the proportion of time spent withdepressive symptoms (two thirds of symptomatic time), is inagreement with other series (Judd et al., 2003b; Kupka et al.,2007; Paykel et al., 2006).

Table 3Weighted mean percentage visits (ITT, 72 weeks).

Affective state % 95% CI

Not euthymic 36.6 33.1–40Sub-syndromic 24.7 21.4–28.1Depressive 17.6 14.5–20.7Hypomania 4.5 2.7–6.2Mixed symptoms 2.7 1.5–3.8

In episode 25.8 21.8–29.7Depressive 12.1 9.2–15.1Manic 2.2 1.2–3.2Hypomanic 8.2 6.1–10.3Mixed 3.3 1.9–4.6

Euthymic 63.4 59.9–66.9

Abbreviation: ITT, intention to treat.

toms in a cohort of bipolar disorder outpatients in Spain: Adoi:10.1016/j.jad.2009.12.006

Fig. 3. Type of symptoms in the visits (n=213).

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6. Sub-syndromal and minor symptoms

In the assessment of time in days with episode, minordepression and hypomanic episode were diagnosed accord-ing to DSM-IV-TR criteria (criteria A in the case of minordepression). Our method for collection of data may havehampered symptom identification. This could be particularlythe case whenever hypomanic or mixed symptoms did notfulfill criteria for episode. Patients may have presented mildunnoticed symptoms of this type during a few days, whichotherwise could have been detected on formal psychometricevaluation. It may also occur that patients “forget” thesesymptoms, neither describing them in the visits nor request-ing help from the psychiatrist. Other reports have pointed outthe difficulties in recalling hypomanic symptoms, notconsidered abnormal by the patients, in contrast withdepressive symptoms (Kupka et al., 2007; Post et al., 2003).We have combined recall by the patients and significantother, psychometric and clinical evaluation and review ofdischarge reports to minimize gaps of information.

According to pre-specified criteria, sub-syndromal symp-toms have been assessed in the visits, focusing in the previousweek. As in other reports assessing the proportion of visitswith symptoms (Frye et al., 2006), we found sub-syndromalsymptoms approximately in 25% of follow-up visits. Only1.4%, of our patients experienced sub-syndromal symptomsin all visits. In other cohorts with different methods, patientspresented sub-syndromal or minor symptoms approximatelyone third of the time (Birmaher et al., 2006; Joffe et al., 2004;Judd et al., 2003a, 2002; Paykel et al., 2006; Post et al., 2003).

Like other researchers (Kupka et al., 2007), we found thesame proportion of visits in episode and with sub-syndromalsymptoms. Other studies described an increased proportionof time with sub-syndromal or minor symptoms than in full-blown episode (Judd et al., 2003a, 2002; Paykel et al., 2006).

7. Associated variables

We performed several analyses to assess the relationshipbetween time in episode and proportion of visits in euthymiaand non-euthymia and various socio-demographic andclinical parameters. We are fully conscious that associations

Please cite this article as: De Dios, C., et al., Time spent with sympprospective, 18-month follow-up study, J. Affect. Disord. (2009),

cannot be considered causal. Corrections have been applied formultiple comparisons. We tried to limit the interrelatedvariables in regression analyses — for instance, EEAG score(axis V) has been excluded, since it comprises a clinical statusassessment; nevertheless, there are still interrelated variables.

As in other naturalistic longitudinal studies (Judd et al.,2003b, 2002; Nolen et al., 2004; Paykel et al., 2006), we foundno significant relationship with socio-demographic variablessuch as gender, age, age of onset, household type, educationallevel or job skill. Many other reports have analyzed therelationship between affective status and gender in bipolardisorder. Several studies have found a significant associationbetween female sex and increased risk of depressive episodes(Robb et al., 1998; Roy-Byrne et al., 1985), more episodes andmore risk of rapid cycling (Coryell et al., 1992), and speciallymore mixed symptoms (Akiskal et al., 1998; Benazzi, 2003;Cassidy and Carroll, 2001; Himmelhoch et al., 1976; Post et al.,1989; Suppes et al., 2005; Swann et al., 1997). Other studiesdid not disclose any relationship between gender and courseof disease in bipolar disorder (Judd et al., 2003a, 2002;Kessing, 2004; Paykel et al., 2006).

We split as different variables the total number of pre-vious episodes— excluding the last year before inclusion, andthe number of episodes in the last year. As in previous studies(Gitlin et al., 1995; Kessing et al., 2004; Nolen et al., 2004;Paykel et al., 2006; Tohen et al., 2006), our data showed thatboth variables were associated with an increased risk ofaffective symptoms at follow-up.

As expected, symptoms indicating more severe psycho-pathology at baseline were significantly related with affectivestatus. Suicidal ideation at recruitment was related to moresymptomatic days at follow-up, and with a higher percentageof visits in depressive episode.

In our series, a seasonal pattern was associated to anincreased probability of being euthymic at baseline, and thisfavorable association appeared to persist during follow-up,with a lower percentage of visits in episode. This seems to beat odds with a recent work, according to which a seasonalcourse is related to an increased predominance of depressiveepisodes (Goikolea et al., 2007). However, our baselineassessment might have been influenced by the time of theyear at which the evaluation took place.

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We found that a better social adjustment was associatedwith lower risk of affective symptoms at follow-up. Otherstudies have similar findings (Judd et al., 2003a, 2002). Likeother authors (Ellicott et al., 1990), we also realized that thepresence of psychosocial stress at baseline was associatedwith more days with affective symptoms at follow-up.

In our data, the bipolar disorder subtype had no impact ontime with symptoms. Several previous studies show that typeII bipolar disorder patients spend more time with symptomsthan type I patients (Judd et al., 2003b; Mantere et al., 2008),but this is not the case in other published research (Joffe et al.,2004; Kupka et al., 2007; Post et al., 2003).

We found no association between time with symptomsand other clinical variables, such as psychiatric comorbidity,time of treatment with mood stabilizing agents, predominantpolarity or initial polarity.

8. Variables related to the presence of sub-syndromalsymptoms

In our study, better social adaptation was associated witha lower percentage of visits with sub-syndromal symptoms,whereas the presence of family history of psychiatricdisorders increased this proportion. In the CDS cohort,where a predominance of sub-syndromal symptoms wasobserved, a positive family history of affective disorderspredicted more time with symptoms (Judd et al., 2003a,2002). We have been unable to find other research with thisfinding related to the presence of sub-syndromal symptoms.

The literature does not reveal clear predictors of theappearance of sub-syndromal symptoms in bipolar disorder.Several studies could not find differences in gender, age ofonset, or duration of disease (Judd et al., 2002; MacQueenet al., 2003; Paykel et al., 2006). It does seem to be anassociation with a worse level of prior functioning, moreduration of index episode and more comorbidity with drugabuse (Judd et al., 2003a, 2002). According to Paykel et al.(2006), predictors of sub-syndromal symptoms were similarto those of major affective episodes. They emphasized thenumber of previous episodes, shorter time since the lastepisode, and worse scores in baseline affective scales. Otherstudies found that psychotic symptoms and more previousepisodeswere associatedwithmore timewith sub-syndromalsymptoms at follow-up (Tohen et al., 2006). None of thesevariables turned out to be significant in our research.

9. Limitations

This study has several strengths and limitations. Strengths:The sample was more representative of the community thanprevious ones. The patients were repeatedly assessed inperson by a psychiatrist during the 18-month follow-up. Eachevaluation was performed by the same clinically experiencedpsychiatrist with a special interest in bipolar disorder andprofound knowledge of the patients, in a naturalistic, publicmental health setting.Moreover, the systematic psychometricassessment supports the clinical data and the informationsupplied by the patients and informants. Limitations: As inother similar studies, the pharmacotherapy of the patientswas naturalistic. Themethod of data collection regarding daysin episode used retrospective data gathering from a relatively

Please cite this article as: De Dios, C., et al., Time spent with sympprospective, 18-month follow-up study, J. Affect. Disord. (2009),

extended period of time. In several published reports, a lifechart or similar record is filled-in by the patient. This methodhas the advantage of being more accurate, but it biases thesample towards patients ready to make long daily records.

10. Conclusions

In a Spanish bipolar outpatient cohort that was gathered tobe representative of bipolar patients from the community, timewith symptoms was shorter than previously found in tertiarycare settings, but other outcomes were similar to selectedsamples. Our data confirm that patients with bipolar disorderspend considerable time of their course with depressivesymptoms, both sub-syndromal and in episode, in a proportionwhich is surprisingly similar to samples from tertiary centersand severely ill patients.We feel that this points out to the needfor a routine evaluation of sub-syndromal symptoms, prefer-ably in a systematic way, with appropriate diagnostic instru-ments, or with an improved clinical evaluation, in order to gaininsight into the full burden of the disease in our patients. Thisshould be done regardless of the setting, including communitymental health centers.

Role of funding sourceThis study was supported by AstraZeneca Pharmaceuticals only for

statistical analysis. AstraZeneca did not have any role in the study design, inthe collection, analysis and interpretation of data, in writing the report, norin the decision to submit the paper for publication.

Conflict of interestDr. De Dios has received grants and served as consultant, advisor or

speaker for the following entities: AstraZeneca, Bristol-Myers-Otsuka, EliLilly, 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 followingentities: AstraZeneca, Lundbeck, Sanofi-Aventis, and Boëhringer-Ingelheim.

Dr. García has received grants and served as speaker for the followingentities: AstraZeneca, Eli Lilly and Boëhringer-Ingelheim.

Dr. Vieta has received grants and served as consultant, advisor or speakerfor the following entities: Almirall, AstraZeneca, Bristol-Myers Squibb, EliLilly, Forest Research Institute, Glaxo-Smith-Kline, Janssen-Cilag, Jazz,Lundbeck, Merck, Novartis, Organon, Otsuka, Pfizer, Sanofi-Aventis, Servier,Shering-Plough, the SpanishMinistry of Science and Innovation (CIBERSAM),the Seventh European Framework Programme (ENBREC), the StanleyMedical Research Institute, United Biosource Corporation, and Wyeth.

Dr. Soler has no conflict of interest.

Acknowledgment

We thank Dr. Jose Luis Agud, for his useful suggestions andcontributions in the writing of this paper.

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