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Mood Disorder Specifiers
Current Diagnostic and Treatment Challenges in Mood Disorders: Breaking Down the DSM-5

Released: August 26, 2024

Expiration: August 25, 2025

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Key Takeaways
  • The DSM-5 added anxious distress and mixed features specifiers to better define the existing variations among BD and MDD.
  • Although there are FDA-approved treatments for depression in BD, there remains a therapeutic need for mixed features in BD and MDD.
  • Emerging evidence supports the efficacy of certain SGAs and novel therapies to meet this need. 

Despite the fact that mood disorders have been recognized since antiquity and are highly prevalent today, the diagnosis and treatment of these disorders remain a significant challenge. Even unipolar major depressive disorder (MDD), with a prevalence of 8% in the US population, has relatively low diagnostic reliability because of its large range in clinical presentation and overlap with other psychiatric conditions, including bipolar and anxiety disorders. Although the bipolar I disorder (BD-I) diagnosis appears to be a more reliable diagnosis than MDD, bipolar II disorder (BD-II) is somewhat less reliable. Furthermore, the nosology for mood disorders in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5 and DSM-5-TR) has continued to evolve with important implications in the treatment of these disorders.

Mood Specifiers in DSM-5
Among the changes in DSM-5 from the DSM-IV was the addition of anxious distress and mixed features specifiers to all mood states, including hypomania and mania with depression. The approach of adding transdiagnostic specifiers to all mood states is consistent with the notion that mood disorders can occur on a spectrum—with full mania on one end and major depression on the other. In between, there are many combinations of and variations in mood states. Although the modern conceptualization of mood disorders as existing on a spectrum was proposed in the 1850s with Emil Kraepelin’s work, the DSM’s iterations, until the DSM-5, have treated depression and mania as rather distinct and separate entities. The exception to this was mixed features in bipolar disorder (BD), which previously required meeting specific syndromal criteria for both depression and mania simultaneously. This combination was rarely, if ever, encountered. In the DSM-5 and DSM-5-TR, only 3 symptoms of the opposite pole are necessary to meet, and this can occur in depression as well as mania or hypomania.

The validity of these new specifiers is still somewhat controversial, but they do present implications in the course of these disorders, including treatment and outcomes. For example, most patients with bipolar depression meet criteria for anxious distress, as do 50% to 75% of patients with MDD. Severe anxious distress is associated with higher rates of substance use, poor functioning, and more severe illness in both BD and MDD. In addition, severe anxious distress and agitation are associated with mixed states and suicidality in MDD. Patients with a major depressive episode (MDE) and less severe anxious distress often respond to selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs), but not bupropion, but more severe anxiety with depression may require adjunctive treatment with benzodiazepine or second-generation antipsychotics (SGAs). Newer treatments like transcranial magnetic stimulation and ketamine also appear to be effective in treating MDD with anxious distress. Electroconvulsive therapy is still the gold standard for treating the most severe MDEs with anxious distress in both bipolar and unipolar depression. Psychedelics are also being actively investigated in the treatment of severe anxiety with depression.

Mania and Hypomania
Although mania and hypomania are frequently responsive to antipsychotics and mood stabilizers, the predominant mood state in BD is depression. In BD-I, the ratio of time spent in MDE vs mania is 3:1, whereas this ratio is as high as 40:1 for depression vs hypomania in BD-II. Although there are many options for the treatment of mania and hypomania, there remains a large unmet need for effective treatments of MDE in BD. Currently, only 5 medications are approved by the FDA to treat depression in BD-I: combination olanzapine plus fluoxetine, quetiapine, lurasidone, cariprazine, and lumateperone. Only quetiapine and lumateperone are approved by the FDA to treat depression in BD-II.

Mixed Features
Mixed features in BD and MDD also represent a significant treatment challenge. Although there are many SGAs approved by the FDA to treat acute manic and mixed states, studies have focused on mixed features in mania. As of this writing in August 2024, there are limited data and no specific FDA approvals for treating mixed states in MDD. Mixed features in MDD suggest a disorder on the bipolar spectrum and, therefore, requires caution with the use antidepressant monotherapy. On the other hand, the limited available data do suggest that SGAs, such as lurasidone, may be effective treating mixed features in MDD. Ketamine may also be beneficial.

What Lies Ahead
In conclusion, the evolving nosology of mood disorders as outlined in the DSM-5 and DSM-5-TR, with the addition of transdiagnostic specifiers such as anxious distress and mixed features, reflects a more nuanced understanding of the spectrum of mood states. These changes acknowledge the complexity of and overlap between different mood disorders, offering a more flexible framework for diagnosis and treatment. The implications of these new specifiers are significant, influencing treatment strategies and outcomes. For instance, the recognition of anxious distress in MDE necessitates tailored therapeutic approaches, including the use of SSRIs, SNRIs, and adjunctive treatments for more severe cases. Similarly, the treatment of mixed features in BD and MDD requires careful consideration of the bipolar spectrum, with emerging evidence supporting the efficacy of certain SGAs and novel therapies like ketamine. As research continues to evolve, these refinements in the DSM-5-TR are crucial steps toward more precise and effective management of mood disorders—ultimately improving patient care and outcomes.

Your Thoughts
How helpful do you find the new specifiers in the DSM-5-TR to be when diagnosing and treating patients with BD or MDD? You can get involved in the conversation by answering the polling question or posting a comment below.

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