Bipolar Depression Research Review

Major Depressive Disorder With Mixed Features and Treatment Response to Lurasidone: A Symptom Network Model

Goldberg JF, et al. J Affect Disord. 2020;277:1045-1054.

Background
To investigate the symptom network structure of major depressive disorder (MDD) with mixed features and implications for treatment.

Methods
In this post hoc analysis of a previously reported randomized trial, patients meeting DSM-IV TR criteria for MDD presenting with 2 or 3 manic symptoms (DSM-5 mixed features specifier) were randomized to 6 weeks of double-blind treatment with lurasidone 20-60 mg/day (n = 109) or placebo (n = 100). The network structure of symptoms at baseline and their treatment moderating effects were investigated.

Results
Network analyses showed that both “elevated mood” (YMRS item 1) and “increased motor activity energy” (YMRS item 2) were associated with “sleep disturbance” (“bridge” symptom) and the depressive symptom cluster. The presence of both “elevated mood” and “increased motor activity energy” at baseline predicted significantly less improvement in MADRS and CGI-S score at Week 6 with lurasidone (vs placebo) compared with patients without these manic symptoms at baseline. The network model also showed “rapid/pressured speech” (YMRS item 6) at baseline predicted improvement in both manic and depressive symptoms with lurasidone vs placebo treatment.

Conclusions
This post hoc analysis describes the symptom network structure of MDD with mixed features in a patient sample at the study baseline. Specific manic symptoms were found to be linked to sleep disturbance (characterized as a “bridge” symptom), which in turn linked the manic and depressive symptom clusters. The presence (vs absence) of the specific manic symptoms we identified moderated the antidepressant and antimanic effects of lurasidone in the treatment of MDD with mixed (subthreshold hypomanic) features.

Clinical Commentary by Roger McIntyre MD, FRCPC
Mixed features are a new nosological entity introduced in the DSM-5. Mixed features are known to affect between 25% and 60% of persons with MDD or bipolar disorder. Lurasidone has demonstrated efficacy in randomized controlled trials in the treatment of bipolar depression and MDD with mixed features. Efficacy and safety in mixed features are of extraordinary clinical relevance, not only because they are commonly encountered, but also because conventional antidepressants exhibit suboptimal efficacy and, in many cases, amplify the underlying affective disturbance.

Investigators in this study conducted an interesting and sophisticated “symptom network model.” The nub of a symptom network model determines which symptoms “march in the same direction” more than others. Healthcare professionals know that depression is a highly heterogeneous phenotype with more than 1000 distinct combinations of symptoms possible using the DSM polythetic criteria.

As it has been previously established that lurasidone is effective and safe in adults with MDD with mixed features, it is of conceptual and clinical relevance to know which symptoms are more tightly coupled together than are others. Unsurprisingly, there was a partial correlation between sleep disturbance in mania and depression. It was also noted that decreased need for sleep was associated with “elevated mood” and “increased motor activity energy.” The investigators also found that targeting specific manic symptoms connecting sleep disturbance with depressive and manic symptoms would be expected to result in improvement of symptoms present in MDD with mixed features. Investigators also reported that the depressive and manic symptoms in MDD with mixed features interact with one another and do not operate independently.

A limitation of the original study is that the definition of MDD with mixed features overlaps with—but is not identical to—the criteria presented in the DSM-5 (ie, 2-3 hypomanic symptoms vs 3 or more with the allowance of overlapping symptoms).

Clinical Insights

• Mixed features in adults with MDD are commonly encountered in clinical practice and research populations and are known to have a suboptimal response to conventional antidepressants.
• Conceptually, and unsurprisingly, sleep disturbance in MDD with mixed was a “bridge” symptom that influenced depressive outcomes.
• It is a testable hypothesis that the efficacy of lurasidone in MDD with mixed features is related to its ability to improve disturbance in critical bridge symptoms (eg, sleep) as well as having therapeutic effects on depressive and manic symptoms directly.

Summary
Lurasidone is safe and effective as monotherapy in the treatment of adults with MDD and mixed features. The Florida Psychotherapeutic Practice Guidelines for MDD list lurasidone as a treatment option for MDD with mixed features. MDD with mixed features is intercorrelated; efficacy of lurasidone may be, in part, related to its targeting of symptoms that intersect depression and mania.

Clinical Commentary by Sanjay Gupta, MD
Since Dr. McIntyre provided an excellent discussion of MDD with mixed symptoms and the study design above, this section will focus on the clinical implications of the findings. Based on DSM-5, the threshold of MDD with mixed features requires 3 of 7 specified manic/hypomanic symptoms to be present during a majority of days of the current episode of major depression. It is important for healthcare professionals to move to the next level—identify mixed features in patients with episodes of MDD—so treatment can be directed in a more precise manner. Although this study has the limitations of a post hoc analysis, it is the first to use the network modeling approach to understand the connection between depressive symptom clusters and the effects of specific manic symptoms like elevated mood, rapid speech, and increased psychomotor energy. Based on this study there are symptom markers that are predictors of a better response to lurasidone.

Clinical Insights

• To improve clinical outcomes in mood disorders healthcare professionals should pay attention to the following:
  • In patients presenting with MDD symptoms, obtain a good longitudinal history including family psychiatric history to assess for a bipolar diathesis.
  • When a diagnosis of MDD is made, look for mixed features.
• Sleep is a bridge symptom between depressive and manic symptoms. Specifically, decreased need for sleep bridges the depressive symptom group with the manic symptom group. Healthcare professionals should ask about sleep when assessing for MDD with the mixed specifier.
• The largest effect of lurasidone was seen in those patients in whom increased psychomotor energy and elevated mood were absent, suggesting that this is an important predictor of lurasidone response in improving depressive symptoms in MDD with mixed features.
• The presence of pressured speech was a predictor of improvement with lurasidone of both mania and depressive symptoms in those with MDD with mixed features patients.
• There is documentation in the literature regarding the link between chronic recurring MDD and metabolic issues like obesity, insulin resistance, diabetes, and dyslipidemia. This has been recently highlighted in a study by Watson and colleagues in the American Journal of Psychiatry and discussed in detail by McIntyre and colleagues in the editorial section of the same issue. The bottom line is prevention of obesity and its related downstream complications like diabetes in this population may improve MDD treatment outcome. In summary, MDD treatment strategy should also include prevention and treatment of metabolic issues. Since “metabolism metastasizes to the brain,” the favorable metabolic profile of lurasidone makes it particularly advantageous in these patients.
• In 2017, Petri and colleagues, in the Journal of Bipolar Disorders, also postulated that obesity in patients with MDD is probabilistic for bipolar disorder. They found that in those with MDD with obesity, 20% met criteria for bipolar disorder, 50% met the criteria for angst bipolar spectrum, and 13% for mixed features using the DSM-5 criteria or the Research Diagnostic Criteria. Dr. McIntyre has an extensive discussion on this subject in the same issue in the debate section.

Summary
This study provides important tips for healthcare professionals to manage patients with MDD with the mixed specifier such as assessing for decreased need for sleep. Absence of elevated mood and increased psychomotor activity is a predictor of improved outcome of lurasidone treatment of depressive symptoms. The overall favorable metabolic profile of lurasidone is a key virtue of this drug. It is important that healthcare professionals instruct patients to take lurasidone with meals to ensure appropriate absorption.