Treatment of mixed features in bipolar disorder

Abstract

Mood episodes with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)-defined mixed features are highly prevalent in bipolar disorder (BD), affecting~40% of patients during the course of illness. Mixed states are associated with poorer clinical outcomes, greater treatment resistance, higher rates of comorbidity, more frequent mood episodes, and increased rates of suicide. The objectives of the current review are to identify, summarize, and synthesize studies assessing the efficacy of treatments specifically for BD I and II mood episodes (ie, including manic, hypomanic, and major depressive episodes) with DSM-5-defined mixed features. Two randomized controlled trials (RCTs) and 6 post-hoc analyses were identified, all of which assessed the efficacy of second-generation antipsychotics (SGAs) for the acute treatment of BD mood episodes with mixed features. Results from these studies provide preliminary support for SGAs as efficacious treatments for both mania with mixed features and bipolar depression with mixed features. However, there are inadequate data to definitively support or refute the clinical use of specific agents. Conventional mood stabilizing agents (eg, lithium and divalproex) have yet to have been adequately studied in DSM-5-defined mixed features. Further study is required to assess the efficacy, safety, and tolerability of treatments specifically for BD mood episodes with mixed features.

Cariprazine efficacy in bipolar I depression with and without concurrent manic symptoms: post hoc analysis of 3 randomized, placebo-controlled studies

“…In this post hoc analysis of 3 pooled phase II/III randomized, double-blind, placebo-controlled trials in patients with bipolar depression, more than half of the patients (58.4%) met the criterion for concurrent manic symptoms (YMRS total score ≥4 at baseline); this is relatively consistent with previously reported prevalence rates for mixed symptoms, which can range from 11% to 70% depending on the study and criteria used. 8,9,11,12,16 In patients with concurrent manic symptoms, sleep and irritability items had the highest mean baseline scores; this is consistent with previous reports as sleep and irritability have been identified to be common manic symptoms occurring in patients with bipolar depression. 12,16,38 Previous reports have also identified that patients with bipolar depression and mixed symptoms are more likely to be female compared with patients without manic symptoms 12,16,36 ; however, in our analyses, the sex distributions were similar between patient subgroups.…”

“…12,16 Using this broader definition of "with mixed features" in patients with bipolar depression, several studies have suggested that atypical antipsychotics may be an effective treatment in this patient population [35][36][37] ; however, it should be noted that the majority of these studies have been performed post hoc. 8,9 Our analysis was designed in a similar manner; to be identified as having concurrent manic symptoms, patients had baseline YMRS total score ≥4 but without requiring any minimum number of manic symptoms.…”

“…The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV-TR) 6 required the contemporaneous presence of a threshold manic and major depressive episode; however, this definition was found to be too restrictive as it did not reflect the range of presentations for bipolar disorder and excluded patients who were experiencing either a major depressive, manic, or hypomanic episode with varying degrees of subsyndromal symptoms of the opposite mood state. [7][8][9] To be more clinically relevant, the definition was broadened in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) 10 with the "with mixed features" specifier, defined as patients meeting criteria for either a major depressive, manic, or hypomanic episode with 3 or more symptoms (without meeting the full criteria as previously required by DSM-IV-TR) of the opposite mood state. Using various modified DSM-5 definitions, it has been estimated that up to 40% (depending on source) of patients with bipolar disorder will experience mixed mood symptoms during manic, hypomanic, or depressive episodes.…”

“…Using various modified DSM-5 definitions, it has been estimated that up to 40% (depending on source) of patients with bipolar disorder will experience mixed mood symptoms during manic, hypomanic, or depressive episodes. 8,9,11,12 The presentation of bipolar depression with mixed features is complex, and there is debate in the literature on whether the symptoms of mixed features are fully captured by the DSM-5 diagnostic criteria. [13][14][15] It should be noted that a number of studies have suggested that the presence of as few as 3 symptoms or less may be sufficient to define a mixed population 12,16 ; as such, the criteria for mixed features remains an iterative process.…”

“…There is evidence that atypical antipsychotics, which can lower the severity of both depressive and manic symptoms, may be able to treat bipolar depression with mixed symptoms. 8,9 It has also been hypothesized that atypical antipsychotics that have affinity for receptors that are thought to modulate depression, such as dopamine D 3 and serotonin 5-HT 1A , may be effective treatments for bipolar depression. 21,22 To this end, a panel of experts have recently recommended that atypical antipsychotics should be considered as the initial treatment for patients with mixed depression.…”