Diagnostic criteria are not always useful to discriminate major depression with anxious distress (ADS-D; Diagnostic and Statistical Manual for Mental Disorders, version-5 [DSM-5] criteria) from mixed depression (Koukopoulos’ criteria; KMX-D). So, clinicians need alternative tools to improve their diagnostic ability and to choose the most appropriate treatment. The aim of the present study is to identify socio-demographic and clinical features that discriminate patients with ADS-D from those with KMX-D.

Two hundred and forty-one consecutive outpatients with unipolar (51%) and bipolar (49%) disorder, fulfilling DSM-5 criteria for a current major depressive episode (MDE) and with a 21-item Hamilton Depression Rating Scale score ≥ 14, were recruited and treated in a prospective observational study.

Ten percent of patients met criteria for KMX-D, 22% ADS-D, and 37% for both. Irritable premorbid temperament, mixed depression polarity at onset, mixed depression recurrence, and a high number of mania symptoms at intake were typical features of patients with KMX-D. Depressive polarity at onset, a low number of mania symptoms at intake, and generalized anxiety disorder comorbidity were typical features of patients with ADS-D. Multinomial logistic regression confirmed that higher rate of irritable temperament and higher Young Mania Rating Scale total score differentiated patients with KMX-D from patients with pure MDE.

Our findings suggest some clinical features that could help differentiate between ADS-D and KMX-D in patients meeting both conditions and to select the appropriate treatment. However, the small sample size may have limited the power to detect differences between the groups. Further research is needed to confirm the results of present study.

Epidemiological, clinical, and treatment response characteristics of major depression with anxious distress (ADS) are quite similar to those of mixed depression, but no study investigated the symptom interplay of these conditions.

To analyze the correlations among symptom criteria for major depression with ADS and for mixed depression using a network analysis.

Two hundred and forty-one outpatients with major depression were consecutively recruited. DSM-5 criteria for major depression with ADS or with mixed features (MF) and Koukopoulos’ criteria for mixed depression (MXD) were assessed using a structured clinical interview.

A total of 58.9% of patients met DSM-5 criteria for major depression with ADS, 48.5% for MXD, and 2.5% for major depression with MF, so that the symptoms of this specifier were excluded from the network analysis. The most frequent symptoms were difficulty concentrating due to worries (57.7%), feeling keyed up or on edge (51%) (major depression with ADS), and psychic agitation or inner tension (51%) (MXD). Psychic agitation or inner tension had a central position in the network and bridged MXD to major depression with ADS through feeling keyed up or on edge.

Criteria for major depression with ADS and for MXD are partially overlapping, with psychic agitation or inner tension and feeling keyed up or on edge that feature in both conditions and are difficult to distinguish in clinical practice. The clarification of the relationship between these two psychopathological conditions could bring important implications for diagnosis, prognosis, and treatment of depressive episodes.