An Overview of Depressive Disorder With Mixed Features

Major Depressive Disorder with Mixed Features — A Review

An Overview of Depressive Disorder With Mixed Features
Posted on:June 28, 2020

Last Updated: August 9, 2020

Time to read: 4 minutes

Depressive disorder with mixed features (DMX), also known as a mixed episode, a mixed state or agitated depression, is a term used in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) to describe a condition in which the symptoms of mania or sub-syndromal mania occur during the depressive disorders of either Major Depressive Disorder or Bipolar I or II disorder.

Mixed depression deserves its own diagnostic identity, with inner psychic agitation as its central feature, even if the DSM system needs to be overhauled in the process. Only then can we meet Aubrey Lewis’ challenge to be both useful and valid in our nosology. [Koukopoulos A, 2014]

The disorder can be conceptualised as lying at the cusp between depression and mania.

Currently, only one treatment guideline exists for major depressive episode with mixed features (i.e., the Florida Best Practice Psychotherapeutic Medication Guidelines for Adults [2015], available for download here.

In this article, we summarise the recent guidelines published by Stahl S et al 2017.

  1. Antidepressant treatment in patients with DMX may be associated with non-response and may result in a worsening of sub-syndromal manic symptoms associated with the depression.
  2. Approximately 13-20% of individuals with unipolar depression and mixed features will eventually meet diagnostic criteria for bipolar I or bipolar II disorder.
  3. Agitated depression (a major depressive episode with psychomotor agitation) is proposed to be a form of mixed depression as other symptoms of hypomania are often present.
  4. Mixed depression is especially common in children and adolescents, and this may contribute to the risk of antidepressant-induced suicidality. Thus, children and adolescents presenting with major depression should be screened and monitored for any (hypo)manic symptoms, suicidality, and family history of mood disorder. It is important to avoid antidepressants until hypomania, and a positive family history of bipolar traits is ruled out.
  5. All patients who receive antidepressants for a major depressive episode should be monitored for signs of abnormal behavioural activation or psychomotor agitation, which may indicate a DMX.

Due to the non-specificity of the DSM-5 criteria in diagnosing DMX and the overlap of symptoms in other disorders, alternative criteria have been proposed.

According to Koukopoulos: Along with a major depressive episode, at least three of the following symptoms must be present:

  • inner tension/agitation
  • racing or crowded thoughts
  • irritability or unprovoked feeling of rage
  • absence of signs of retardation
  • talkativeness
  • dramatic description of suffering or frequent spells of weeping
  • mood lability and marked emotional reactivity
  • early insomnia.

DMX has been associated with:

  • Family history of bipolar spectrum disorders
  • Suicidality
  • Antidepressant-induced mania
  • Rapid cycling
  • Young age of onset
  • Long duration of illness
  • Poor prognosis
  • Severe depression
  • Antidepressant resistance
  • Females
  • Comorbid anxiety
  • Comorbid substance use disorder
  • Impulse control disorders

Scales to assist in the diagnosis of DMX:

Bipolar Depression Rating Scale (BDRS) 

  • Clinician-administered assessment of current symptoms

The Koukopoulos Mixed Depression Rating Scale (KMDRS)

  • Clinician rating scale specifically designed to assess DMX symptoms cross-sectionally,

Hypomania Interview Guide (HIG)

Mini-International Neuropsychiatric Interview (M.I.N.I.)

Clinically Useful Depression Outcome Scale with DSM–5 Mixed (CUDOS–M)

Hypomania Checklist (HCL–32)

  • Patient self-report that screens for lifetime (hypo)manic symptoms—this does not assess mixed episodes

Mood Disorder Questionnaire (MDQ)

  • Patient self-report that screens for a lifetime(hypo)manic symptoms

Altman Mania Rating Scale


General Principles:

  • Rule out organic conditions – e.g. Hyperthyroidism, Traumatic brain injury etc [learn more about medical evaluation in mood disorders]
  • Rule out substance use or medication-induced mixed states e.g. corticosteroids, L-Dopa etc
  • Assess for the presence of any symptoms of (hypo)mania and family history of mood disorder, including bipolar disorder, before initiating treatment
  • If antidepressants are initiated; monitor for symptoms of hypomania and suicidality.
  • Venlafaxine may have the highest risk of suicidality in children and adolescents.

Algorithm for the management of DMX

There is uncertainty around the use of antidepressants in patients with mixed depression of any type (unipolar, BP-II, or BP I) due to minimal efficacy but also the potential to worsen the mixed state.

Medication choice:

  • Tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) may carry the highest risk of causing a treatment-emergent affective switch. In contrast, bupropion and some selective serotonin reuptake inhibitors (SSRIs) may have a lower risk of an affective switch.
  • A lower dose of antipsychotic medications may be required in mild to moderate DMX.

Continuation therapy:

  • Continue the treatment if one of the recommended acute treatments led to prompt remission from the most recent mixed depressive episode.
  • The preferred strategy is for continuous rather than intermittent treatment with oral medication to prevent new episodes.


Depressive disorder with mixed features is a condition in which sub-syndromal hypomanic features occur as part of a depressive syndrome.

This condition can easily be missed. Treatment of depressive mixed features with antidepressants has important prognostic implications which clinicians should be aware of.

Clinicians should be vigilant for red flags of depressive mixed features, the treatment of which requires mood stabilisers and or antipsychotic medications for optimal outcomes.

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