Original article Diagnostic conversion to bipolar disorder in unipolar depressed patients participating in trials on antidepressants J. Holmskov a,b, *, R.W. Licht b,c , K. Andersen a , T. Bjerregaard Stage d , F. Mørkeberg Nilsson e , K. Bjerregaard Stage a , J.B. Valentin b , P. Bech f , R. Ernst Nielsen b,c a Institute of Clinical Health, University of Southern Denmark, Department of Psychiatry, Odense, Region of Southern Denmark, Denmark b Unit for Psychiatric Research, Aalborg University Hospital, Psychiatry, Aalborg, Denmark c Department of Clinical Medicine, Aalborg University, Aalborg, Denmark d Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark e Psychiatric Department, Geriatric Psychiatric Unit, Psychiatric Centre Ballerup, Capital Region, Denmark f Psychiatric Research Unit, Psychiatric Centre North Zealand, Copenhagen University Hospital, Copenhagen, Denmark 1. Introduction Mental illnesses are generally understood as spectrums differentiated into disorders according to presence or absence of specific symptoms [1]. The International Classification of Mental and Behavioral Disorders 10th version (ICD-10) [2] and the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) [3] have divided the affective spectrum into depressive disorders (or unipolar depressive disorders) and bipolar disorders. Besides symptomatic differences and differences in the course of illness, the pharmacological treatment strategies differ to some degree between unipolar depressive disorder and bipolar disorder [4]. However, a substantial number of patients originally diagnosed as suffering from unipolar depressive disorder subse- quently develop mania or hypomania thereby ‘‘converting’’ into bipolar disorder. The risk of conversion is observed to be between 0.5 and 1.0% per year [5,6]. The search for predictors of conversion from unipolar depres- sive disorder to bipolar disorder is of clinical relevance, since patients at high risk should be followed more closely or at least be informed about the possible risk of conversion. Hypomanic symptoms below diagnostic threshold have been suggested as clinical risk factors for diagnostic conversion [7] alongside rapid onset of depression [8,9], pharmacological-associated hypomania and mood-congruent psychotic features [9]. A relatively high risk of conversion has also been shown in adolescents suffering from European Psychiatry 40 (2017) 76–81 A R T I C L E I N F O Article history: Received 29 June 2016 Received in revised form 19 August 2016 Accepted 19 August 2016 Available online Keywords: Affective disorders Unipolar depression Mania and bipolar disorder Criteria Antidepressant Epidemiology A B S T R A C T Objective: In unipolar depressed patients participating in trials on antidepressants, we investigated if illness characteristics at baseline could predict conversion to bipolar disorder. Method: A long-term register-based follow-up study of 290 unipolar depressed patients with a mean age of 50.8 years (SD = 11.9) participating in three randomized trials on antidepressants conducted in the period 1985–1994. The independent effects of explanatory variables were examined by applying Cox regression analyses. Results: The overall risk of conversion was 20.7%, with a mean follow-up time of 15.2 years per patient. The risk of conversion was associated with an increasing number of previous depressive episodes at baseline, [HR 1.18, 95% CI (1.10–1.26)]. No association with gender, age, age at first depressive episode, duration of baseline episode, subtype of depression or any of the investigated HAM-D subscales included was found. Limitations: The patients were followed-up through the Danish Psychiatric Central Research Register, which resulted in inherent limitations such as possible misclassification of outcome. Conclusion: In a sample of middle-aged hospitalized unipolar depressed patients participating in trials on antidepressants, the risk of conversion was associated with the number of previous depressive episodes. Therefore, this study emphasizes that unipolar depressed patients experiencing a relatively high number of recurrences should be followed more closely, or at least be informed about the possible increased risk of conversion.  C 2016 Published by Elsevier Masson SAS. * Corresponding author at: Unit for Psychiatric Research, Aalborg University Hospital, Psychiatry, Mølleparkvej 10, 9000 Aalborg, Denmark. Tel.: +45 976 436 09. E-mail address: jho@rn.dk (J. Holmskov). Contents lists available at ScienceDirect European Psychiatry jo u rn al h om epag e: h ttp ://ww w.eu ro p s y- jo ur n al.co m http://dx.doi.org/10.1016/j.eurpsy.2016.08.006 0924-9338/  C 2016 Published by Elsevier Masson SAS.