Diagnostic and therapeutic implications of the DSM-5 mixed features specifier

The DSM-5, concept of major depressive disorder (MDD) with mixed features (MF) and the risk for such patients to convert to bipolar disorder (BPD) type I (BPD I) or BPD type II (BPD II) were highlighted at Psych Congress by Joseph Goldberg (Clinical Professor of Psychiatry, Icahn School of Medicine at Mount Sinai, New Rochelle, NY). He outlined the characteristics of MF, how to diagnose and monitor them, and reviewed the evidence for pharmacotherapy decision-making in order to optimize therapeutic outcomes.

The DSM-5 mixed features specifier

Patients with mixed features are likely to be younger and experience more rapid switching between depression and mania

Kraepelin’s notion that MF falls along a continuum from pure mania to pure depression has been rediscovered, said Professor Goldberg. The DSM-5 MF specifier replaces the DSM‑IV‑TR mixed episodes specifier; and the diagnosis is based on the occurrence of more than three symptoms of opposite polarity that do not overlap with the syndromal pole. Overlapping symptoms; such as distractibility, indecision, insomnia and irritability, are not counted twice.1 MF can occur in:

  • BPD I (mania or depression)
  • BPD II (hypomania or depression)
  • (unipolar) MDD

Patients with MF develop an illness with more rapid switching between depression and mania and at a younger age than those without2, and are more likely to have co-occurring heart disease.3 In addition, they are more likely to report alcohol and substance misuse3 and experience more functional impairment and unemployment, explained Professor Goldberg. He advised to watch for polarity conversion in MDD‑MF, especially in the first 5 years.

Two‑thirds of individuals with bipolar depressed episodes have concomitant manic symptoms.2 The prevalence of DSM‑5 MF — identified from the Young Mania Rating Scale (YMRS), Montgomery–Åsberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HAM‑D) — has been found to be 26% for MDD, 34% for BPD I, and 33.8% for BPD II.3

Making a diagnosis of mixed features

Presence of mixed features worsen the prognosis

To diagnose MF, it is critical to obtain a careful past history, said Professor Goldberg, together with corroborative accounts from relatives and associates, if possible. Ask about symptoms of depression, mania and hypomania systematically:

  • symptoms of depression in relation to Sleep, Interest, Guilt, Energy, Concentration, Appetite, Psychomotor activity, Suicidal ideation (SIGECAPS)
  • symptoms of mania and hypomania in terms of Distractibility, Impulsivity, Grandiosity, Flight of ideas, Activity increase, Sleep deficit, Talkativeness (DIGFAST)

The severity of the illness can be determined and monitored using a variety of measurement scales, including MADRS, HAM‑D, and the Patient Health Questionnaire (PHQ‑9) for MDD, and YMRS for mania.

Avoid antidepressants for bipolar I or II and major depressive episode with mixed features

Adverse events of medications; such as antidepressant withdrawal symptoms, akathisia and insomnia, can be confused with affective symptoms and need to be excluded, cautioned Professor Goldberg, as do other potential causes; such as substance misuse, steroid intake and thyroid disease.

Pharmacotherapy for MDD‑MF

Avoid antidepressants for a BPD I, BPD II and major depressive episode with MF; and consider whether antidepressants might be worsening MDD‑MF,4,5 advised Professor Goldberg. Treatment with antidepressants may lead to greater manic symptom severity in bipolar depression accompanied by manic symptoms and do not speed up the time to recovery relative to treatment with mood stabilizers alone,4 he explained.

Monotherapy with certain atypical antipsychotics is recommended for MDD-MF

No psychotropic agents are FDA-approved for MDD‑MF, but Professor Goldberg highlighted guideline recommendations produced by a panel of experts based on the few studies available and cumulated clinical experience. The panel recommends monotherapy with certain atypical antipsychotics as the first-line treatment.6

Professor Goldberg advocated the use of evidence-based treatments for mood episodes with MF, and highlighted a study showing some benefit from electroconvulsive therapy in 70% of patients with severe drug‑resistant BPD‑MF.7

  1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, Fifth edition. Arlington. VA: APA; 2013.
  2. Goldberg J, et al. Am J Psych 2009;166(2):173–81.
  3. McIntyre R, et al. J Affect Disord 2015;172:259–64.
  4. Goldberg J, et al. Am J Psych 2007;164(9):1348–55.
  5. Frye M, et al. Am J Psych 2009;166(2):164–72.
  6. Stahl S, et al. CNS Spectr 2017;22(2):203–19.
  7. Medda P, et al. J Clin Psych 2015;76(9):1168–73.
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