Mixed depression: Toward a conceptual framework

INTRODUCTION

Literature indicates that mixed symptoms are common, clinically consequential, and frequently under-recognized in major depressive disorder (MDD).^1-3 In clinical practice, individuals with major depressive episode (MDE) may display a few hypomanic or activation symptoms. When these occur in a depressive episode, the clinical presentation is referred to as mixed depression to differentiate it from ‘pure depression’. In the current classification, ICD-11 lacks recognition of subthreshold mixed features in patients diagnosed with MDD. DSM-5 introduced the specifier “with mixed features” for depressive episode, but its purpose is undermined by the paradoxical exclusion of the commonly observed mixed symptoms such as psychomotor agitation, irritability, and lability. These criteria mark an improvement, but still hinder the optimal recognition, with important clinical implications.^4,5

Historical descriptions of agitated depression are broadly similar to the concept of mixed depression. Since the advent of DSM-III in 1980, mood disorders were bifurcated into unipolar and bipolar disorders with an overemphasis on polarity (depression vs mania) that did not acknowledge mixed states in a meaningful way. Further, both DSM-III/DSM-IV and ICD-10 criteria for mixed episodes were impractical to fulfil.^1,2 Consequently, mixed presentations became uncommon and under-represented, till their partial revival with DSM-5.

The mixed symptoms when they occur in individuals diagnosed with unipolar depression are either subsumed entirely in the construction of MDD, are dismissed just as a depressive epiphenomenon, or misattributed to concurrent anxiety or personality disorders. Despite diagnostic system revisions, a significant proportion of such patients with mixed symptoms remain undetected. To resolve this crisis, there is a need to bridge the gap between diagnostic constructs and clinical reality, thereby improving patient outcomes.

This paper discusses mixed symptoms in major depression, examining the conceptual and nosological frameworks, along with empirical evidence and critical gaps. At the outset, it should be noted that mixed states exist on a spectrum that includes manic episodes; however, this paper focuses on mixed symptoms in depression, particularly in the context of MDD.

To the extent feasible, the discussion centers on MDEs in MDD, but where separate findings on MDD are not available, it incorporates findings from studies on MDEs with combined samples of unipolar and bipolar depression. All such instances are clearly outlined in the paper.

Furthermore, it is also useful to differentiate the following terms often used in literature, to understand their usage throughout this paper:

• Mixed features specifier: Current manic, hypomanic, or MDE that also includes ≥3 clinically significant symptoms from the opposite pole, as defined in DSM-5

• Mixed symptom: any symptom in a mood episode from opposite polarity or is considered to represent a mixed state, irrespective of whether the classificatory system recognizes it or not, e.g., irritable rather than depressed mood, agitation rather than retardation in case of MDE

• Mixed states (as a phenomenological label): Any clinical state in which manic/hypomanic and depressive symptoms co-occur or have admixtures of varying degree, regardless of how a given classification system labels it. As per the preponderance of symptoms, a depressive mixed state or manic mixed state can be delineated.⁶

• Mixed episode (current use in ICD-11; historical use in DSM-IV/ICD-10): A mood episode meeting full syndromic criteria for both manic and depressive syndromes either simultaneously or in very rapid alternation.

THE RISE AND THE FALL LEADING UP TO A RECENT REVIVAL

Sporadic descriptions of mixed states can be found in the writings of Falret, Griesinger, Heinroth, and Flemming. Emil Kraepelin, in the first edition of his textbook, made a mention of “Melancholia Activa” with more specific types emerging later on, such as “involutional melancholia.”

The severe, anxious, and agitated depression of later life (involutional melancholia) was considered by Kraepelin to be a disease distinct from depressions under manic-depressive illness (MDI). A pivotal change in this viewpoint came from the work of Georges Dreyfus, who was a colleague of his. Through meticulous observational studies, Dreyfus argued that involutional melancholia was not a separate entity but rather a manifestation of MDI.^7,8 This was based on the hallmark symptoms, profound agitation, anxiety, panic, and restlessness, noting that they were similar to mixed states of MDI that were described in an earlier work of Wilhelm Weygandt.

Working in Kraepelin’s supervision, Weygandt had previously concluded that mixed states are a norm in the context of MDI.^7-9 He also developed the now-landmark scheme to explain the mixed states (based on independent dimensions of mood, thought, and volition). As many as six subtypes of mixed states were described, such as agitated depression (negative affect and thought, with increased motility), and depression with flight of ideas (negative affect and volition, with increased thought processes).

Based on the work by Dreyfus (underpinned by Weygandt’s framework), Kraepelin performed a major revision in the 8th Edition (1913) of his textbook, classifying the “involutional melancholia” under the umbrella of MDI.⁷ Further, Kraepelian perspective treated varying admixtures of manic and depression as a core principle of mood disorders and subsumed all of them under MDI.

In successive decades, the dominant narrative transitioned into the narrower, more precisely defined mood episodes of either polarity under MDI. Agitated depression continued to be recognized till the 1970s, for example, in the Research Diagnostic Criteria (RDC)¹⁰, and was later absorbed under major depression in classificatory systems.

With the advent of DSM-III (1980), the diagnostic systems formally bifurcated MDI into unipolar and bipolar disorder, moving to a Leonhardian perspective. This theoretical shift posed an identity crisis for the middle ground of mixed states, though by that time, the mixed states were thought to be too uncommon to merit consideration.

DSM-III-R and DSM-IV attempted to accommodate the phenomenon with a narrowly defined “mixed episode” (requiring simultaneous, full syndromal criteria for mania and major depression every day for a week), a threshold that captured only a fraction of clinically mixed states and reinforced the impression of rarity.

ICD-10 recognized mixed states in two places:

• F31.6 Bipolar affective disorder, current episode mixed: requires syndromal mania and syndromal depression present most days for at least 2 weeks, either simultaneously or in very rapid alternation- broader in phenomenology than DSM-IV’s “mixed episode,” but confined to categorical diagnosis in bipolar affective disorder.

• F38.0 Mixed affective episode: a single mixed episode classified under “other mood disorders.” Despite existing on paper, it was sparingly used and offered limited guidance.

CLINICAL SIGNIFICANCE AND IMPACT

Meta-analytic evidence indicates that approximately one-quarter of patients with depression present with admixtures of mixed symptoms.¹¹ Mixed states, in general, are one of the important drivers of adverse course and poor outcomes in mood disorders.

Patients of both MDD and BD with mixed features experience an earlier age of onset, increased risk of psychiatric hospitalization, and higher rates of comorbid anxiety or substance use.^12-14 The mixed state during MDE has been linked with suicidal risk in patients with mood disorders.^14,15 Longitudinally, the mixed depression manifests more frequent and severe episodes, and spends less time in euthymia. Depression with mixed features has an association with female gender, rapid cycling, and family history of BD, besides an increased risk of conversion to BD diagnosis. Mixed features across mood episodes showed partial stability in a study on patients with BD.¹⁶ Further, mixed features could be potentially associated with treatment-emergent affective switches or other iatrogenic risks on conventional antidepressants with higher switch potential.^17,18

MIXED DEPRESSION AND DSM-5/ICD-11: MOVING FORWARD, MISSING THE MARK

This contemporary nosology underrepresents the clinical reality of mixed depression. This impedes accurate documentation and confounds research. There is a fundamental divergence in the approach to mixed depressive states between the two classificatory systems, viz, DSM-5¹⁹ and ICD-11,²⁰ each presenting its own critical challenges.

The DSM-5 made visible changes to integrate dimensionality of mixed states by introducing “mixed features specifier” for MDE (applied to both MDD and BD), which is a pragmatic step to acknowledge dimensionality, but the purpose is ultimately defeated due to fundamentally flawed and paradoxical criteria for “mixed features specifier.” The DSM-5 mandates that for a depressive episode to be specified with mixed features, a patient must experience at least three ‘non-overlapping’ manic symptoms. It deliberately excludes symptoms that were considered core to the concept of mixed depression based on the flawed rationale of their historical inclusion under depression. Consequently, a depressed patient with severe, distressing agitation and intense irritability is excluded from receiving the specifier. Further, the symptoms of elevated or expansive mood and inflated self-esteem or grandiosity that are listed in the mixed features specifier have been found to be highly uncommon in mixed depressive states.^1,2,21

Unlike DSM-5, ICD-11 preserves a category of mixed episodes under BD, defined by simultaneous or rapidly alternating depressive and manic symptoms. Interestingly, ICD-11 BD mixed episode criteria says that when depressive symptoms predominate, some of the most common contrapolar features are irritability, distractibility, increased verbal output, and psychomotor agitation, precisely the features that DSM-5 excludes from its mixed features specifier in MDE. ICD-11 lists mixed episodes under the heading of BD. Compared to DSM-5 BD-MDE with mixed features, however, ICD-11 lists more inclusive and non-prescriptive contrapolar symptoms under BD mixed episode, but it imposes a higher threshold by requiring both polarities to alternate or co-exist at the syndromic level.

ICD-11 does not acknowledge mixed specifiers, unlike DSM-5. Therefore, for patients presenting with mixed symptoms in MDE, there is no specifier or diagnostic code in ICD-11 to capture this complexity.

Available literature reports a higher prevalence based on a broader research-based criterion compared to the prevalence defined by the DSM mixed features specifier in MDD. The pooled prevalence was 23.8% in MDD depressive episode (and 35.2% in bipolar depressive episode) for studies using broader criteria of any three contrapolar features.¹¹ On the other hand, a review of studies using DSM-5 defined mixed features reported a pooled prevalence of 11.6% for MDE (and 26.8% for manic episodes).²²

Coming to Asian literature, a multicentric study of Indian patients with first-episode depression reported 16% DSM-5-defined mixed features.²³ In a study from North India, 21.5% of patients with unipolar depression met DSM-5 mixed-features criteria, similar to the 23.7% reported for bipolar depression in the same study.²⁴ Another large sample from Korea reported a much lower prevalence of DSM-5 mixed features in MDE, particularly in MDD (1.7%), compared with those in bipolar disorder (BD) (15.6%). In contrast, when broader criteria were applied, prevalence rates were substantially higher (MDD: 19%, BD: 61.8%).²⁵

Thus, the clinicians are caught between a DSM-5 system that misrepresents mixed depression by defining it too narrowly and an ICD-11 system that is more inclusive in contrapolar features but overlooks the subsyndromal mixed states.

CONCEPTUAL FOUNDATIONS OF MIXED DEPRESSION

KOUKOPOLOUS’S MIXED DEPRESSION VS AGITATED DEPRESSION

Mixed depression has been conceptually differentiated into forms with and without overt motor agitation. The former corresponds to agitated depression as defined in the Research Diagnostic Criteria (RDC).¹⁰

By contrast, Koukopoulos’s mixed depression without psychomotor agitation is characterized primarily by “inner psychic unrest” or “psychic agitation” in the absence of markedly increased motor activity.^33,35 Along with a MDE, the presence of at least three of the following eight symptoms is required to define Koukopoulos’s mixed depression: (1) inner tension or agitation; (2) racing or crowded thoughts; (3) irritability or unprovoked rage; (4) absence of psychomotor retardation; (5) talkativeness; (6) dramatic expression of suffering or frequent spells of weeping; (7) mood lability and marked emotional reactivity; and (8) early insomnia. These patients often report unbearable psychic suffering, marked mood lability, and heightened emotional reactivity.

The concept of Koukopolous’s mixed depression is in alignment with the historical concept, though research to validate the scale is limited. At least one study demonstrated internal consistency and inter-rater reliability to be adequate for the Koukopolous Mixed Depression Rating Scale (KMDRS).³³

OVERLAP OF MIXITY AND ANXIETY SPECIFIERS IN DSM-5 MIXED DEPRESSION

There is some research to indicate that patients with excitatory symptoms in MDD are often categorized under anxious distress rather than as mixed depression in DSM-5, and that their criteria have some overlapping aspects.³⁶ Anxious distress specifier requires presence of at least two of the following symptoms for most days: (a) feeling keyed up or tense; (b) feeling unusually restless; (c) difficulty concentrating because of worry; (d) fear that something awful may happen; and (e) feeling that the individual might lose control of himself or herself.

A network analyses for symptom relationships support this diagnostic entanglement, showing that symptoms like irritability, agitation, and anxiety cluster together, bridging depressive and hypomanic domains.³⁷ Together, these findings highlight that some criteria in anxiety specifiers are not clearly separable from mixed depression, leading to under-recognition of mixed states.

DIMENSIONAL OR NON-CATEGORICAL APPROACHES TO MIXED STATES

Several-dimensional frameworks attempt to conceptualize mixed states.²⁶ To start, it is useful to add that none of these approaches is without limitations, and these do not provide a complete explanatory framework. While some are supported by some data, the evidence remains limited for others, and key issues of validity and clinical utility persist

• Additive (combinatorial) approach: These approaches view mixed states as the co-occurrence of depressive and manic symptoms in varying combinations, reflecting overlap between opposite poles. Kraepelian-Wegandt framework^9,38 is an example of this approach. The DSM-5 criteria also involve an additive approach.¹⁹

• Emergent (non-combinatorial) approaches: In contrast to the above, the Vienna school conceptualized mixed states as emergent biological conditions of contradictory arousal and affect. This approach views mixed states as a qualitatively new state that is sustained by dysregulated systems of arousal and affective drive.^26,39

• Affective Temperament Model: This emphasizes that mixed episodes can emerge when acute mood states interact with temperamental traits, e.g., cyclothymia or hyperthymia. For instance, depression in a hyperthymic temperament may present as mixed depression.^40,41

• Staging and spectrum perspectives: Duffy’s clinical staging model treats mood disorders as evolving across phases, with mixed presentations marking unstable transition points rather than discrete categories.⁴² Benazzi’s spectrum work situates mixed depression as the linking phenotype along a unipolar–bipolar continuum. Together, these approaches imply gradations that are missed by rigid categorical thresholds.⁴³

• RDoC framework: The Research Domain Criteria (RDoC)⁴⁴ position mixed states across multiple functional domains: negative valence (distress, anhedonia), positive valence (reward dysregulation), arousal/regulatory systems (hyperactivation), and cognitive control (racing/crowded thoughts). This reflects multi-system dysfunction.

• HiTOP model: The Hierarchical Taxonomy of Psychopathology (HiTOP)⁴⁵ situates mixed states within the internalizing spectrum, but overlapping with bipolarity and disinhibited externalizing. Symptoms like irritability, agitation, and emotional lability are transdiagnostic disturbances in mood regulation and arousal

• Network theory: From a dynamic perspective driven by network theory,⁴⁶ mixed states are viewed as unstable but self-reinforcing symptom networks, where activation in one cluster (e.g., irritability, agitation) amplifies or sustains depressive affect, creating a perpetuating cycle. A recent study on patients with acute depression across MDD and BD found that mixed symptoms were the most central and highly interconnected nodes in the network, particularly agitation, followed by irritability. Further, mixed symptoms such as appetite gain and hypersomnia were associated with BD rather than MDD, suggesting a possible stratification within mixed states.⁴⁷

BRIDGING CLINICAL GAPS IN MIXED DEPRESSION

CONCLUSION

Mixed states, particularly those in MDD, remain clinically unrecognized and nosologically fractured. Contemporary perspectives increasingly recognize the nuanced and complex nature of mixed depression. Both ICD-11/DSM-5 represent progress, but critical challenges remain in both classificatory systems. Further, significant empirical gaps persist, particularly in the context of MDD, with limited treatment trials to guide its management. There is a need to move toward a more conceptually coherent and clinically useful framework for mixed depression, with implications for diagnosis and treatment.