It was additionally reported that the mixed features group with MDD may be more likely to experience medical disorders, such as cardiovascular disease, when compared to those without mixed features.
The pertinence of this observation is axiomatic and underscored further by a recent report on behalf of the American Heart Association identifying bipolar disorder and major depressive disorder as independent Tier II risk factors for cardiovascular disease.15 In addition to conceptualizing the mixed features patient as a greater risk for premature death by suicide, it needs to be emphasized that death due to chronic, non-communicable disorders, is a cause of premature mortality.16,17 The mortality risk due to cardiovascular disease invites the need for risk factor modification, emphasis on diet, lifestyle modification, as well as the selection and sequencing of pharmacological agents that give prior to those agents with lower probability of aggravating cardiovascular risk (e.g. weight gain).
Currently, there are no large, randomized, double-blind, placebo-controlled trials that have primarily sought to determine the efficacy, safety, and tolerability of a conventional antidepressant in the treatment of MDD with mixed features according to DSM-5 criteria. Available evidence, however, that adults with MDD and subthreshold hypomanic symptoms and/or experiencing agitated depression exhibit suboptimal treatment responses to conventional antidepressants and often require polypharmacological regimens with other treatment agents (e.g. hypnotics, anxiolytics). It has also been observed that individuals with depression and mixed features are often treated with atypicals, antipsychotics, as well as other agents with mood stabilizing properties.14,18
The only study that has ever been published evaluating a treatment for MDD with mixed features was a recent publication evaluating lurasidone (Latuda) in adults with MDD experiencing a depressive episode as well as 2-3 hypomanic symptoms.19 This study concluded that after six weeks of therapy, lurasidone was superior to placebo in efficacy in reducing overall depressive symptom severity (as measured by MADRS) as well as reducing anxiety symptoms and significantly improved overall clinical status and function of treated patients.
Importantly, individuals receiving lurasidone did not experience destabilization (i.e. amplification of hypomanic severity) and instead experienced an improvement in overall hypomanic burden. The favorable effect of lurasidone in this study on both depressive and hypomanic symptoms in adults with MDD and mixed features extends a previous observation that lurasidone (FDA approved for bipolar depression) is also efficacious in adults with bipolar depression and mixed features. Lurasidone did not worsen weight or metabolic status, a critical observation given the cardiovascular risk inherent in this subtype.
The recent update of the Florida Medicaid guidelines for the treatment of bipolar disorder emphasized that in treating adults with mixed features, it is important to begin with guiding principles for assessing suicidality, psychiatric and physical comorbidity, psychosis and cognitive function.20 For MDD with mixed features, treatment options may include manualized-based psychotherapies (e.g. cognitive behavioral therapy), the use of a conventional antidepressant or a second-generation antipsychotic and/or conventional mood stabilizer lithium. It must be emphasized that the evidence supporting the foregoing recommendations is either non-existent or minimal at best.
Taken together, mixed features are commonly encountered in clinical practice, they are not pathognomonic with bipolar disorder as they also affect a large percentage of adults with MDD. The mixed features specifier identifies a subpopulation that is often misdiagnosed, has greater illness burden, and greater debased human capital. Clinicians are also encouraged to use measurement-based care to identify individuals with mixed features and to consult recent guidelines (i.e. Florida guidelines) on best practice algorithms in treating such a condition.
Roger McIntyre, MD, is head of the Mood Disorders Psychopharmacology Unit at the University Health Network, in Toronto, Canada. He is also a member of the Psychiatry Advisor editorial board.
Disclosure: McIntyre has served as an advisor or consultant for Sunovion. Lurasidone is manufactured by Sunovion.
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- McIntyre RS. Practical Approaches in the Management of Bipolar Depression: Overcoming Challenges and Avoiding Pitfalls. Evidence-Based Treatment of Bipolar Disorder, Bipolar Depression, and Mixed Features. J Fam Pract 2015; 64(6 Suppl):S16-S23.
- Perugi G, et al. Mixed features in patients with a major depressive episode: the BRIDGE-II-MIX study. J Clin Psychiatry. 2015;76(3):e351-e358.
- Malhi GS, et al. Mixed state discrimination: a DSM problem that wont go away? J Affect Disord. 2014; 158:8-10.
- 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? Psychiatry Clin Neurosci. 2015; 69(2):109-16.
- Goldberg JF, et al. Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2009; 166(2):173-81.
- Suppes T, et al. Mixed hypomania in 908 patients with bipolar disorder evaluated prospectively in the Stanley Foundation Bipolar Treatment Network: a sex-specific phenomenon. Arch Gen Psychiatry 2005; 62(10):1089-96.
- Modell S, Huber J, Holsboer F, Lauer CJ. The Munich Vulnerability Study on Affective Disorders: risk factors for unipolarity versus bipolarity. J Affect Disord. 2003; 74(2):173-84.
- McIntyre RS, et al. The prevalence and illness characteristics of DSM-5-defined “mixed feature specifier” in adults with major depressive disorder and bipolar disorder: Results from the International Mood Disorders Collaborative Project. J Affect Disord. 2014; 172C:259-64.
- Olfson M, et al. Trends in office-based mental health care provided by psychiatrists and primary care physicians. J Clin Psychiatry. 2014; 75(3):247-53.
- Dilsaver SC, et al . Gender, suicidality and bipolar mixed states in adolescents. J Affect Disord. 2005; 87(1):11-6.
- Dilsaver SC, Chen YW. Social phobia, panic disorder and suicidality in subjects with pure and depressive mania. J Affect Disord. 2003; 77(2):173-7.
- Freedman R, et al. The initial field trials of DSM-5: new blooms and old thorns. Am J Psychiatry 2013; 170(1):1-5.
- Akiskal HS, et al. Agitated “unipolar” depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy. J Affect Disord. 2005; 85(3):245-58.
- Goldstein BI, et al. Major Depressive Disorder and Bipolar Disorder Predispose Youth to Accelerated Atherosclerosis and Early Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation 2015; 132: 965-986.
- McIntyre RS. Overview of managing medical comorbidities in patients with severe mental illness. J Clin Psychiatry. 2009; 70(6):e17.
- Arch Gen Psychiatry. 2001; 58(9):844-50.
- Maj M, et al. Agitated depression in bipolar I disorder: prevalence, phenomenology, and outcome. Am J Psychiatry 2003; 160(12):2134-40.
- Suppes T, et al. Lurasidone for the Treatment of Major Depressive Disorder With Mixed Features: A Randomized, Double-Blind, Placebo-Controlled Study. Am J Psychiatry. 2015; doi: appi.ajp.2015.15060770.
- Florida Best Practice Psychotherapeutic Medication Guidelines for Adults. Florida Medicaid Drug Therapy Management Program for Behavioral Health. 2015.