Hunter Yost, MD

Assessment of suicidal risk in adolescents is a solemn professional obligation that involves obtaining as much information as possible from family members or caregivers. Evaluation of mood disorders is an essential part of the assessment.

When DSM-V took a significant step beyond previous editions to include the mixed features specifier for unipolar major depression, the already contentious area of child and adolescent mood disorders became even more challenging. It is also an opportunity, however, to expand our understanding of mood disorders and to provide safer treatment for affected youths.

Numerous authors have reviewed Kraepelin’s original conceptualization of mixed features. In recent decades, research on mixed features has re-established Kraepelin’s thinking and has provided insights that challenge established dogma about depression and mania and show how overlooking mixed symptoms can increase suicide attempts and completed suicides in adolescents and adults.

Another major contributor to our understanding of mixed features in depressive states is Athanasios Koukopoulos. Verdolini and colleagues

 place one of Koukopoulos’s core criteria, mood lability (or affective lability), which they define as “the predisposition to rapidly reversible and marked shifts in affective states that are extremely sensitive to environmental events with intense behavioral responses” (as distinguished from DSM-defined “mood reactivity” in response to positive stimuli), near the center region of their Revised Affective Spectrum that bridges the continuum from pure depression to pure mania. These researchers explain that affective lability was excluded from the DSM-5 “with mixed features” specifier, possibly leaving many cases of mixed depression undiagnosed and subsequently inadequately treated.

Studies clearly indicate that mixed presentations are the rule rather than the exception in adolescents:

• “This study showed that bipolar spectrum disorders in youth are episodic disorders most often characterized by subsyndromal episodes and, less frequently, by syndromal episodes, with mainly depressive and mixed symptoms and rapid mood changes.”

• “The mixed state was the most common presentation for bipolar adolescents who were in the midst of an MDE at the time of presentation to a mental health clinic.”

Mixed features: non-overlapping vs overlapping

What counts as a mixed feature? DSM-5 has expanded the concept substantially over DSM-IV, allowing the specifier to be used for both depressive and manic episodes yet restricting it to three symptoms each of the opposite pole of 4 days’ duration or 2 weeks’ duration, respectively (

). The non-overlapping mixed feature criteria have limited support in the literature.

In contrast, the so-called overlapping criteria listed in 

 are supported in the literature. Given that the majority of adolescents present as depressed with mixed features rather than with pure depressive or manic episodes, our assessment of youth at risk may need to extend beyond currently defined DSM mixed criteria. 

 found that “irritability, distractibility and psychomotor agitation were present in more than 90% of the subjects with mixed depression.”

 the frequency of DSM-5 defined “MDD with mixed features” as a percentage of all major depressive episodes (MDEs) is 10%; however, the frequency of “mixed depression” using Koukopoulos’s criteria as a percentage of all MDEs is 50%.

When an adolescent presents with depression, mixed features are the symptoms that are least likely to be assessed. For various reasons, “major depression” has remained the default diagnosis for youth with suicidal ideation, while widely available validated screening tools such as the Mood Disorder Questionnaire (MDQ) for Parents of Adolescents remain underutilized.

Hypomanic symptoms are rarely volunteered by patients or their parents when youths present with suicidal ideation or an attempt. Eliciting mixed symptoms and subsyndromal hypomanic symptoms requires additional time and effort to delve beyond depressive symptoms to the hidden story of mixed features, where the real diagnosis may lie. Frequently, the diagnosis is not simply uncomplicated unipolar depression. There is often a cursory rule-out comment in the medical record such as “patent denies manic symptoms” with no mention of mixed features.

Many youths who receive a misdiagnosis of MDD are given repeated courses of antidepressants without benefit, with worsening of depression and mixed features, or “mixity,” and increased suicidal activation. BalÃ¡zs and colleagues5 conclude: “Irritability and psychomotor agitation were the strongest predictors of suicide attempt. From a public health standpoint, our data highlight the necessity of detecting and treating mixed (bipolar) depression in the prevention of suicidal behavior.”

Other studies also underscore the link between mixed features and suicide:

• “More prevalent in suicidal versus non-suicidal subjects by multivariate analysis were: depressive symptoms, hyper-emotionality, younger-at-first-affective-episode, family suicide history, childhood mood-swings, and adolescence low self-esteem.”

• “Those with MDD and mixed features were 5 times more likely to experience suicidal ideation and 3 times more likely to engage in suicidal behavior, both of which were statistically significant increases.”

• “Suicidality might be conferred by a combination of both the excited (mixed) depressive and agitated (melancholic) clusters,” and, “Our analyses delineate a mixed depressive substrate at risk for suicidality.”

All too frequently in the medical record there is a lack of consideration of the course or trajectory of prodromal symptoms. Faedda and colleagues

 write: “Precursors of bipolar disorder include mood lability, subsyndromal and major depression, subsyndromal hypomanic symptoms with or without major depression, cyclothymia and bipolar not otherwise specified, major depression with psychotic features, and other psychotic disorders. Bipolar disorder was also predicted by juvenile onset of major depression as well as frequency and loading of hypomanic or depressive symptoms.” This suggests that mixed features may precede and predict a bipolar disorder. Ghaemi

 considers the course of prodromal symptoms to be the most important diagnostic validator in conjunction with family history.

While there are screening tools to elicit bipolar symptoms-such as the MDQ for Parents of Adolescents, Young Mania Rating Scale, 

University of Pittsburg Risk Calculator for Kids

, Parent General Behavior Inventory (GBI), and Parent-Child Mania Rating Scale-10 (CMRS-10)-until recently there have been no screening tools for mixed features. Tavormina

 writes: “The knowledge of the clinical features of the mixed states and of the symptoms of the ‘mixity’ of mood disorders is crucial: to mis-diagnose or mis-treat patients with these symptoms may increase the suicide risk and worsen the evolution of mood disorders. The rating scale ‘G.T. MSRS’ has been designed to improve the clinical effectiveness of both psychiatrists and GPs by enabling them to make an early ‘general’ diagnosis of mixed states.” This scale awaits further validation but is noteworthy for an increased recognition of mixed features.

 have provided validation for the Koukopoulos Mixed Depression Rating Scale (KMDRS): “KMDRS was a reliable and valid instrument to assess MxD (mixed depression) symptoms.”

In the past, the standard of practice was to treat any symptoms of depression with an antidepressant. Often this would occur without an adequate differentiation between unipolar and bipolar depression. The new paradigm elaborated by 

 is to treat any subsyndromal manic symptoms and/or dysphoric agitation with an antipsychotic and/or mood stabilizer rather than an antidepressant. While there are no FDA-approved medications for mixed features, treatment guidelines for bipolar depression are probably most applicable to depression with mixed features.

There is general consensus that antidepressants are contraindicated as monotherapy when clear manic symptoms are present; however, consensus is less clear as to the role of antidepressants in the presence of mixed features or even the existence of mixed features in a given adolescent. Koirala and associates

 conclude: “Findings of the study indicate that a substantial proportion of young MDD subjects share BPD illness characteristics. These high risk subjects, if treated with antidepressants, need to be monitored for development of BPD.” In addition, Akiskal and colleagues

 note that “reports of increased risk of suicidal ideation and/or behavior in some depressed patients treated by antidepressant monotherapy or combinations thereof might be attributed to baseline psychomotor activation/agitation as part of an unrecognized bipolar mixed state.”

Because of the significantly elevated risk of suicide in adolescents with mixed features, it would behoove psychiatrists to err on the side of overdiagnosing mixed features and considering mood stabilizers and/or second-generation antipsychotics as first-line therapy rather than antidepressants, especially when the patient has a first-degree relative with a bipolar condition. Given the heritability of bipolar disorder with a first-degree relative, this is a crucial factor in any evaluation.

I propose that mixed features be included as a primary risk factor for suicide in adolescents. Every teenager who presents with depressive symptoms should be evaluated for mixed features before unipolar depression is diagnosed and antidepressants are prescribed.

Dr Yost provides telemedicine psychiatric services in several states for both adults and adolescents in hospitals and clinics. He reports no conflicts of interest concerning the subject matter of this article.

 Verdolini N, Menculini G, Perugi G, et al. Sultans of swing: a reappraisal of the intertwined association between affective lability and mood reactivity in a post hoc analysis of the BRIDGE-II-MIX Study. 

 Birmaher B, Axelson D. Four-year longitudinal course of children and adolescents with bipolar spectrum disorder: the Course and Outcome of Bipolar Youth (COBY) Study. 

 Dilsaver SC, Benazzi F, Akiskal HS. Mixed states: the most common outpatient presentation of bipolar depressed adolescents? 

 Dilsaver SC, Akiskal HS. “Mixed hypomania” in children and adolescents: is it a pediatric bipolar phenotype with extreme diurnal variation between depression and hypomania? 

 BalÃ¡zs J, Benazzi F, Rihmer Z, et al. The close link between suicide attempts and mixed (bipolar) depression: implications for suicide prevention. 

Clinical Psychopharmacology: Principles and Practice

. Oxford, UK: Oxford University Press; 2018.

 Serra G, Koukopoulos A, De Chiara L, et al. Child and adolescent clinical features preceding adult suicide attempts. 

 McIntyre RS, Ng-Mak D, Chuang C-C, et al. Major depressive disorder with subthreshold hypomanic (mixed) features: a real-world assessment of treatment patterns and economic burden. 

 Akiskal HS, Benazzi F. Psychopathologic correlates of suicidal ideation in major depressive outpatients: is it all due to unrecognized (bipolar) depressive mixed states? 

 Faedda GL, Marangoni C, Serra G, et al. Precursors of bipolar disorders: a systematic literature review of prospective studies. 

 Tavormina G. Clinical utilisation of the “G.T. MSRS,” the rating scale for mixed states: 35 cases report. 

 Sani G, VÃ¶hringer PA, Barroilhet SA, et al. The Koukopoulos Mixed Depression Rating Scale (KMDRS): An International Mood Network (IMN) validation study of a new mixed mood rating scale. 

 Stahl SM, Morrissette DA, Faedda G, et al. Guidelines for the recognition and management of mixed depression. 

 Koirala P, Hu B, Altinay M, et al. Sub-threshold bipolar disorder in medication-free young subjects with major depression: clinical characteristics and antidepressant treatment response. 

 Akiskal HS, Benazzi F, Perugi G, Rihmer Z. Agitated “unipolar” depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy. 

 Takeshima M, Oka T. DSM-5-defined ‘mixed features’ and Benazzi’s mixed depression: which is practically useful to discriminate bipolar disorder from unipolar depression in patients with depression? 

 Koukopoulos A, Sani G. DSM-5 criteria for depression with mixed features: a farewell to mixed depression. 

Hunter Yost, MD

Articles

Mixed Features, Suicide, and Adolescents at Risk