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J Psychiatr Res. 2019 Mar;110:1-8. doi: 10.1016/j.jpsychires.2018.12.006. Epub 2018 Dec 8.

Sub-threshold bipolar disorder in medication-free young subjects with major depression: Clinical characteristics and antidepressant treatment response.

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Center for Behavioral Health, Cleveland Clinic, USA.
Quantitative Health Sciences Center, Cleveland Clinic, USA.
Departments of Psychiatry, Epidemiology, and Internal Medicine, University of Iowa, USA.
Center for Behavioral Health, Cleveland Clinic, USA. Electronic address:



This study, for the first time, compared illness and antidepressant response characteristics of young subjects with major depression (MDD) at low (LRMDD) or high-risk (HRMDD) for developing bipolar disorder with characteristics of young bipolar (BPD) subjects and healthy controls (HC).


One hundred and six young (15-30 yr), medication-free subjects MDD subjects (HRMDD, N = 51; LRMDD, N = 55) were compared with 32 BPD (Type I: 14; Type II: 18) as well as 49 HC subjects. Baseline illness characteristics and frequency of comorbid conditions were examined using Analysis of Variance and Cochran-Armitage trend test. Additionally, in MDD subjects, the effect of open-label antidepressant treatment for up to 24 months with periodic assessments was compared between HRMDD and LRMDD groups for treatment response, remission and (hypo)mania switch while controlling for attrition.


Significant gradation from LRMDD to HRMDD to BPD groups was found for increasing occurrence of alcohol dependence (p = 0.006), comorbid PTSD (p = 0.006), borderline personality traits (p = 0.001), and occurrence of melancholic features (p < 0.005). Antidepressant treatment response was similar between the two groups except that for the 12-month period HRMDD showed a trend for a lower response. Switch to (hypo)mania was infrequent in both groups though the HRMDD showed a higher occurrence of spikes in (hypo)mania symptoms (>25% increase in YMRS scores)(p = 0.04).


Findings of the study indicate that a substantial proportion of young MDD subjects share BPD illness characteristics. These HRMDD subjects, if treated with antidepressants, need to be monitored for development of BPD.




Antidepressant treatment; Bipolar disorder; Depression; Hypomania; Mania; Subthreshold symptoms; Young-adults; Youth

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