Background: Subsyndromal symptoms have been recognized as relevant in the course and outcome of bipolar disorder (BD) patients. Nevertheless, their definition and cutoff points on current depression and mania scales are uncertain. The recently defined International Society for Bipolar Disorders (ISBD) operational criteria for the assessment of the course and outcome of bipolar illness have never been tested until now. Methods: A naturalistic longitudinal follow-up study of up to 5 years included a cohort of 317 DSM-IV-TR BD outpatients. For the first time, we assessed the proportion of visits in different affective states using the ISBD criteria. Secondarily, we compared the results with those obtained applying other cutoff points. Results: Patients were symptomatic in 39.1% (95% CI 35.3–42.9) of the visits. Subsyndromal symptoms, primarily subsyndromal depression, were present in 15.9% of patients (95% CI 13.4–18.4). No significant differences were found between bipolar I patients and bipolar II patients. There were differences in the total percentage of visits in euthymia depending on the cutoff points (p < 0.05). Conclusions: Applying ISBD criteria, bipolar patients have significant clinical morbidity and are often symptomatic, both with threshold symptoms and with subthreshold symptoms, especially with depression. The chosen cutoff points modify the apparent results. Limitations: The cutoff points used have not been validated. Psychopharmacologic treatments were naturalistic.

Keywords:
Outcome, Bipolar illness status definitions, Subsyndromal symptoms, Follow-up study, Diagnosis, Course, Bipolar disorder
1.
Houston JP, Ketter TA, Case M, et al: Early symptom change and prediction of subsequent remission with olanzapine augmentation in divalproex-resistant bipolar mixed episodes. J Psychiatr Res 2010;45:169–173.
2.
Tohen M, Frank E, Bowden CL, et al: The International Society for Bipolar Disorders (ISBD) Task Force report on the nomenclature of course and outcome in bipolar disorders. Bipolar Disord 2009;11:453–473.
3.
De Dios C, Ezquiaga E, Garcia A, Soler B, Vieta E: Time spent with symptoms in a cohort of bipolar disorder outpatients in Spain: a prospective, 18-month follow-up study. J Affect Disord 2010;125:74–81.
4.
Sheehan DV, Lecrubier Y, Sheehan KH, et al: The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59(suppl 20):22–33, quiz 34–57.
5.
Ramos Brieva J, Cordero Villafáfila A: Validación de la versión española de la Escala de Hamilton para la Depresión. Actas Luso Esp Neurol Psiquiatr Cienc Afines 1986;14:324–334.
6.
Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 1961;23:56–62.
7.
Colom F, Vieta E, Martinez-Aran A, et al: Spanish version of a scale for the assessment of mania: validity and reliability of the Young Mania Rating Scale (in Spanish). Med Clin (Barc) 2002;119:366–371.
8.
Young RC, Biggs JT, Ziegler VE, Meyer DA: A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978;133:429–435.
9.
Vieta Pascual E, Torrent Font C, Martinez-Aran A, et al: A user-friendly scale for the short and long term outcome of bipolar disorder: the CGI-BP-M (in Spanish). Actas Esp Psiquiatr 2002;30:301–304.
10.
Bobes J, Gonzalez MP, Bascaran MT, et al: Validation of the Spanish version of the social adaptation scale in depressive patients (in Spanish). Actas Esp Psiquiatr 1999;27:71–80.
11.
Bosc M, Dubini A, Polin V: Development and validation of a social functioning scale, the Social Adaptation Self-evaluation Scale. Eur Neuropsychopharmacol 1997;7(suppl 1):S57–S70, discussion S71–S53.
12.
Berk M, Hallam KT, McGorry PD: The potential utility of a staging model as a course specifier: a bipolar disorder perspective. J Affect Disord 2007;100:279–281.
13.
Frye MA, Yatham LN, Calabrese JR, et al: Incidence and time course of subsyndromal symptoms in patients with bipolar I disorder: an evaluation of 2 placebo-controlled maintenance trials. J Clin Psychiatry 2006;67:1721–1728.
14.
Gopal S, Steffens DC, Kramer ML, Olsen MK: Symptomatic remission in patients with bipolar mania: results from a double-blind, placebo-controlled trial of risperidone monotherapy. J Clin Psychiatry 2005;66:1016–1020.
15.
Tohen M, Greil W, Calabrese JR, et al: Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial. Am J Psychiatry 2005;162:1281–1290.
16.
Tohen M, Bowden CL, Calabrese JR, et al: Influence of sub-syndromal symptoms after remission from manic or mixed episodes. Br J Psychiatry 2006;189:515–519.
17.
Yatham LN, Binder C, Kusumakar V, Riccardelli R: Risperidone plus lithium versus risperidone plus valproate in acute and continuation treatment of mania. Int Clin Psychopharmacol 2004;19:103–109.
18.
Suppes T, Mintz J, McElroy SL, et al: Mixed hypomania in 908 patients with bipolar disorder evaluated prospectively in the Stanley Foundation Bipolar Treatment Network: a sex-specific phenomenon. Arch Gen Psychiatry 2005;62:1089–1096.
19.
Goldberg JF, Perlis RH, Bowden CL, et al: Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP-BD. Am J Psychiatry 2009;166:173–181.
20.
Judd LL, Schettler PJ, Akiskal HS, et al: Residual symptom recovery from major affective episodes in bipolar disorders and rapid episode relapse/recurrence. Arch Gen Psychiatry 2008;65:386–394.
21.
Kessing LV: The prevalence of mixed episodes during the course of illness in bipolar disorder. Acta Psychiatr Scand 2008;117:216–224.
22.
McElroy SL, Keck PE Jr, Pope HG Jr, et al: Clinical and research implications of the diagnosis of dysphoric or mixed mania or hypomania. Am J Psychiatry 1992;149:1633–1644.
23.
Keller M, Lavori P, Coryell W, et al: Differential outcome of pure manic, mixed/cycling, and pure depressive episodes in patients with bipolar illness. JAMA 1986;255:3138–3142.
24.
Goldberg JF, Garno JL, Leon AC, Kocsis JH, Portera L: Rapid titration of mood stabilizers predicts remission from mixed or pure mania in bipolar patients. J Clin Psychiatry 1998;59:151–158.
25.
United States Department of Health and Human Services: Revised definition means millions more have pre-diabetes. Washington, USDHHS, 2004.
26.
White HD, Chew DP: Acute myocardial infarction. Lancet 2008;372:570–584.
27.
Ilic D, O’Connor D, Green S, Wilt T: Screening for prostate cancer. Cochrane Database Syst Rev 2006;3:CD004720.
28.
Bauer M, Glenn T, Grof P, et al: Frequency of subsyndromal symptoms and employment status in patients with bipolar disorder. Soc Psychiatry Psychiatr Epidemiol 2009;44:515–522.
29.
Perlis RH, Ostacher MJ, Patel JK, et al: Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry 2006;163:217–224.
30.
Keller MB, Lavori PW, Kane JM, et al: Subsyndromal symptoms in bipolar disorder: a comparison of standard and low serum levels of lithium. Arch Gen Psychiatry 1992;49:371–376.
31.
Gitlin MJ, Swendsen J, Heller TL, Hammen C: Relapse and impairment in bipolar disorder. Am J Psychiatry 1995;152:1635–1640.
32.
MacQueen GM, Marriott M, Begin H, et al: Subsyndromal symptoms assessed in longitudinal, prospective follow-up of a cohort of patients with bipolar disorder. Bipolar Disord 2003;5:349–355.
33.
Dion GL, Tohen M, Anthony WA, Waternaux CS: Symptoms and functioning of patients with bipolar disorder six months after hospitalization. Hosp Community Psychiatry 1988;39:652–657.
34.
Altshuler LL, Post RM, Black DO, et al: Subsyndromal depressive symptoms are associated with functional impairment in patients with bipolar disorder: results of a large, multisite study. J Clin Psychiatry 2006;67:1551–1560.
35.
Marangell LB, Dennehy EB, Miyahara S, et al: The functional impact of subsyndromal depressive symptoms in bipolar disorder: data from STEP-BD. J Affect Disord 2009;114:58–67.
36.
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;65:231–241.
37.
Bauwens F, Tracy A, Pardoen D, Vander Elst M, Mendlewicz J: Social adjustment of remitted bipolar and unipolar outpatients: a comparison with age- and sex-matched controls. Br J Psychiatry 1991;159:239–244.
38.
Judd L, Akiskal H, Schettler P, et al: Psychosocial disability in the course of bipolar I and bipolar II disorders: a prospective, comparative, longitudinal study. Arch Gen Psychiatry 2005;62:1322–1330.
39.
Shapira B, Zislin J, Gelfin Y, et al: Social adjustment and self-esteem in remitted patients with unipolar and bipolar affective disorder: a case-control study. Compr Psychiatry 1999;40:24–30.
40.
Fagiolini A, Kupfer DJ, Masalehdan A, et al: Functional impairment in the remission phase of bipolar disorder. Bipolar Disord 2005;7:281–285.
41.
Cooke RG, Robb JC, Young LT, Joffe RT: Well-being and functioning in patients with bipolar disorder assessed using the MOS 20-ITEM short form (SF-20). J Affect Disord 1996;39:93–97.
42.
Angst J, Gamma A, Sellaro R, Lavori PW, Zhang H: Recurrence of bipolar disorders and major depression: a life-long perspective. Eur Arch Psychiatry Clin Neurosci 2003;253:236–240.
43.
Benazzi F: Is 4 days the minimum duration of hypomania in bipolar II disorder? Eur Arch Psychiatry Clin Neurosci 2001;251:32–34.
44.
Benazzi F, Akiskal H: The duration of hypomania in bipolar-II disorder in private practice: methodology and validation. J Affect Disord 2006;96:189–196.
45.
Benazzi F: What is hypomania? Tetrachoric factor analysis and kernel estimation of DSM-IV hypomanic symptoms. J Clin Psychiatry 2009;70:1514–1521.
46.
Bauer M, Glenn T, Grof P, et al: Self-reported data from patients with bipolar disorder: frequency of brief depression. J Affect Disord 2007;101:227–233.
47.
Akiskal HS, Djenderedjian AM, Rosenthal RH, Khani MK: Cyclothymic disorder: validating criteria for inclusion in the bipolar affective group. Am J Psychiatry 1977;134:1227–1233.
48.
Frye MA, Helleman G, McElroy SL, et al: Correlates of treatment-emergent mania associated with antidepressant treatment in bipolar depression. Am J Psychiatry 2009;166:164–172.
49.
Smith DJ, Forty L, Russell E, et al: Sub-threshold manic symptoms in recurrent major depressive disorder are a marker for poor outcome. Acta Psychiatr Scand 2009;119:325–329.
© 2012 S. Karger AG, Basel
2012
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.