• major depressive disorder
• bipolar disorder

Background: Current classifications of mood disorders focus on polarity rather than recurrency, thus separating Bipolar Disorder (BD) from Major Depressive Disorder (MDD). There is though increasing evidence that a course of MDD characterized by high number and frequency of major depressive episodes (MDEs) is related to a bipolar diathesis, regardless the occurrence of hypomanic/manic episodes, with implication for clinical practice. Objective: The aim of the present study is to explore the possible relationships between number and frequency of the depressive episodes and clinical variables associated to bipolarity in a sample of MDD patients. Method: The present study is a post-hoc analysis, based on a pooled cohort of MDD patients resulting from the combination of two international, naturalistic and transversal studies, the BRIDGE and the BRIDGE-II-Mix studies. The final total sample included 7055 patients, divided in 4 groups: patients at first mood episode, patients with 1 previous MDE, patients with 2 or 3 MDEs in the past, patients with at least 4 previous MDEs. Patients in the latter group (n= 2977) were in turn subdivided in patients with 1 or less MDE in the last 365 days (low-frequency) and patients with 2 or more MDEs in the last year (high-frequency). Sociodemographic and clinical variables were compared between groups through Chi-square and Student’s t-test. Two stepwise backward logistic regression model were used to identify the predictive value of clinical features on the presence of high number (≥2) and high frequency (≥2) of depressive recurrences. Results: In comparison with low-recurrency patients (≤ 1 MDE in the past), subjects with greater number and frequency of MDEs showed earlier depressive onset, greater burden of BD family history, more atypical and psychotic features, more suicide attempts, more antidepressant (AD) treatment resistance and more hypomanic/manic switches when treated with ADs. Furthermore, highly recurrent patients were more frequently treated with mood-stabilizers and presented higher rates of bipolarity diagnosis, according to Angst criteria. Similarly, high-frequency patients were more related than low-frequency subjects with a bipolar diathesis in terms of BD family history, briefer duration of current MDE, higher rates of mood switches under AD treatment and greater comorbidity, in particular with alcohol-substance use disorders. Among the above-mentioned bipolar features, logistic regression showed that a previous history of AD-induced mania/hypomania, the prescription of mood-stabilizers and a diagnosis of bipolarity according to Angst criteria were variables associated with both high-recurrency and high-frequency depression. Conclusions: High-recurrency and high-frequency MDD patients differed from those with lower number and frequency of MDEs for several clinical variables usually associated with bipolarity. These results support the need to identify, within the wide and heterogeneous range of MDD patients, a subpopulation of subjects with high recurrence and frequency of the episodes. Even in the absence of hypomanic/manic episodes, these patients seem to be similar to those belonging to bipolar spectrum in terms of clinical features and, perhaps, treatment response. The current diagnostic classification of mood disorders based on the polarity of affective episodes, neglects the importance of recurrency and cyclicity (frequency) which are core features of the disease. Future research focusing on the identification of highly recurrent MDD patients may be relevant for the definition of appropriate treatment strategies.