“Evaluation and impact of subthreshold contrapolar symptoms during a Major Depressive Episode in unipolar and bipolar patients”

A considerable proportion of individuals suffering from a major depressive episode (MDE) experience co-occurring subthreshold hypomanic symptoms. Although these presentations - commonly referenced as “mixed depressive states”- have been described since the Classical Age, an operational definition of mixed depression was not included in the official psychiatric nomenclature until 2013 with the introduction of the “with mixed features” specifier (MFS) in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). The MFS – which may be applied to any mood episode (manic, hypomanic, or depressive episode) - denotes the co-occurrence of a threshold mood episode along with subthreshold symptoms of the opposite polarity, providing a less restrictive definition of mixed mood states, compared to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). However, several objections have been raised against the “DSM-5 defined mixed depression”, whose diagnostic validity and accuracy are still debated with conflicting positions. The presence of mixed features during a depressive episode (either in MDD or in BD) has been associated with worse illness course, treatment resistance, and higher suicidal risks, although the generalizability of these outcomes is affected by the heterogeneity of operational definitions used for mixed depression. Thus - far from being a merely speculative issue - a reliable nosologic framework validly accounting for within-MDE subthreshold bipolarity has substantial concrete implications at several levels, from patient’s management to international regulatory agency’s choices. The main object of this doctoral research was to investigate the presence and impact on illness-course of contrapolar symptomatology during an MDE in a multicenter sample of 300 patients with MDD or BD. In order to adopt a dimensional and spectrum-based approach, the current mood symptomatology was assessed by completing the last-month version of the Mood Spectrum‐Self Report‐Current (MOODS‐SR) questionnaire. The first study was aimed to evaluate the differences in mood spectrum between the two main diagnostic groups (MDD vs. BD). We found that (hypo)manic symptoms were endorsed by a large number of patients with BD, but also by a considerable number of patients with MDD. Significant differences between the two groups were restricted to “energy depressive” and “mood manic” MOODS domain scores. In the second study, we disaggregated our sample into three transdiagnostic groups by using a clustering analysis approach based on MOOD-SR scores. Consistent with our hypothesis, we observed an overall disease-severity gradient, paralleling the increasing magnitude of contrapolar symptomatology across the clusters. In the third study reported here, we compared the diagnostic constructs of DSM-5 defined mixed depression and Koukopoulos’ mixed depression (KMxD) in terms of prevalence, associated clinical variables, and discriminative capacity for bipolar depression in patients with an ongoing MDE. We found that the two constructs exhibited an overlapping discriminative capacity for bipolar depression. However, the current diagnostic threshold of DSM-5 MFS did not prove to be adequately inclusive if compared to the greater diagnostic sensitivity of KMxD, which also yielded better association with clinical variables related to mixedness. Overall, the results of these studies confirmed: the high prevalence and clinical relevance of subthreshold hypomania within an MDE regardless of the main diagnosis; the intrinsic inadequacy of the current DSM-5 MFS criteria in describing mixed depressive states; the need for a unitary, dimensional, more descriptive and dynamic approach to affective disorders. Finally, the fourth paper reported in the present thesis is derived from a secondary research project consisting of a survey designed to investigate the attitudes of Italian psychiatrists towards the clinical entity of mixed depression in terms of diagnostic, therapeutic approaches, and psychopathological reference model. The results of the survey indicated: the relevance of mixed depressive presentations in the real-world clinical settings, a poor rating regarding the quality of training on the management of these forms during the residency, a broad disagreement with the DSM-5 operational definition of mixed depression, and a general alignment of prescribing practice for the treatment of mixed states with the recommendations provided by available guidelines.