Anxiety, irritability, and agitation as indicators of bipolar mania with depressive symptoms: a post hoc analysis of two clinical trials

Abstract

Background: Symptoms of anxiety, irritability, and agitation (AIA) are prevalent among patients with bipolar I disorder (BD-I) mania with depressive symptoms, and could potentially be used to aid physicians in the identification of this more severe form of BD-I. Using data from two clinical trials, the aims of this post hoc analysis were to describe the phenomenology of bipolar mania in terms of AIA and depressive symptoms, and to evaluate the influence of these symptoms on the likelihood of remission during treatment.

Methods: Patients with a BD-I manic or mixed episode (Diagnostic and Statistical Manual of Mental Disorders IV criteria) were randomised to 3 weeks of double-blind treatment with asenapine, placebo, or olanzapine (active comparator). Anxiety was defined as a score of ≥3 on the Positive and Negative Syndrome Scale 'anxiety' item, irritability as a score of ≥4 on the Young Mania Rating Scale (YMRS) 'irritability' item, and agitation as a score of ≥3 on the YMRS 'increased motor activity-energy' item. Depressive symptoms were defined as a score of ≥1 on three or more individual Montgomery-Åsberg Depression Rating Scale (MADRS) items, or a MADRS Total score of ≥20.

Results: A total of 960 patients with BD-I were analysed, 665 with a manic episode and 295 with a mixed episode. At baseline, 61.4% had anxiety, 62.4% had irritability, 76.4% had agitation, and 34.0% had all three AIA symptoms ('severe AIA'); 47.3% had three or more depressive symptoms, and 13.5% had a MADRS total score of ≥20. Anxiety, irritability, and severe AIA (but not agitation) were statistically significantly more common in patients with depressive symptoms. Patients with anxiety or severe AIA at baseline were statistically significantly less likely to achieve remission (YMRS total <12). In general, remission rates were higher with asenapine and olanzapine than with placebo, irrespective of baseline AIA or depressive symptoms.

Conclusions: Assessment of AIA symptoms in bipolar mania could enable physicians to identify patients with more severe depressive symptoms, allowing for appropriate intervention. Assessment and monitoring of AIA may help physicians to predict which patients may be harder to treat and at risk for self-harm. Trial registration ClinicalTrials.gov NCT00159744, NCT00159796. Registered 8 September 2005 (retrospectively registered).

Keywords: Agitation; Anxiety; Bipolar disorder; Depression; Irritability; Mixed features; Remission.

Figures

Fig. 1

Venn diagram displaying the overlap of comorbid AIA symptoms in BD-I mania. Sixteen patients (1.7%) were missing a value for one or more AIA symptom at baseline and are not shown on the figure. Anxiety was defined as a PANSS anxiety item score of ≥3 at baseline. Irritability was defined as a YMRS irritability item score of ≥4 at baseline. Agitation was defined as a YMRS increased motor activity–energy item score of ≥3 at baseline. Percentages are calculated from the full analysis set, which comprised 960 patients. AIA, anxiety, irritability, and agitation; BD-I, bipolar I disorder; PANSS, Positive and Negative Syndrome Scale; YMRS, Young Mania Rating Scale

Fig. 2

Incidence of baseline AIA symptoms in BD-I mania, stratified by the number/severity of depressive symptoms. **p < 0.01,
***p < 0.001, Chi squared test. Anxiety was defined as a PANSS anxiety item score of ≥3 at baseline. Irritability was defined as a YMRS irritability item score of ≥4 at baseline. Agitation was defined as a YMRS increased motor activity–energy item score of ≥3 at baseline. Severe AIA was defined as meeting the above criteria for all three AIA symptoms. Patients missing a value for the corresponding symptom at baseline were not included in the analysis. a Based on the number of individual MADRS items with a score of ≥1. AIA, anxiety, irritability, and agitation; BD-I, bipolar I disorder; MADRS, Montgomery–Åsberg Depression Rating Scale; PANSS, Positive and Negative Syndrome Scale; YMRS, Young Mania Rating Scale. a Number of depressive symptoms of 0-2 symptoms versus 3 or more symptoms, and b severity of depressive symptoms baseline MADRS <20 versus ≥ to 20

Fig. 3

Incidence of remission in BD-I mania, stratified by baseline AIA/depressive symptoms. #p-value significant (when adjusted for multiplicity), Chi squared test. Anxiety was defined as a PANSS anxiety item score of ≥3 at baseline. Irritability was defined as a YMRS irritability item score of ≥4 at baseline. Agitation was defined as a YMRS increased motor activity–energy item score of ≥3 at baseline. Severe AIA was defined as meeting the above criteria for all three AIA symptoms. Patients missing a value for the corresponding symptom at baseline were not included in the analysis. Two definitions were used for remission: a YMRS Total score of <12 at Day 21 (upper figures); and a YMRS Total score of <8 at Day 21 (lower figures) (observed cases). Depressive symptoms were defined in two ways: ≥3 individual MADRS items with a score of ≥1, or a MADRS Total score of ≥20 at baseline. AIA, anxiety, irritability, and agitation; BD-I, bipolar I disorder; MADRS, Montgomery–Åsberg Depression Rating Scale; PANSS, Positive and Negative Syndrome Scale; YMRS, Young Mania Rating Scale. a Presence or absence of baseline AIA symptoms and b presence or absence of baseline depressive symptoms

Fig. 4

Incidence of remission by treatment group in BD-I mania, stratified by baseline AIA/depressive symptoms. Anxiety was defined as a PANSS anxiety item score of ≥3 at baseline. Irritability was defined as a YMRS irritability item score of ≥4 at baseline. Agitation was defined as a YMRS increased motor activity–energy item score of ≥3 at baseline. Severe AIA was defined as meeting the above criteria for all three AIA symptoms. Patients missing a value for the corresponding symptom at baseline were not included in the analysis. Two definitions were used for remission: a YMRS Total score of a Presence of baseline AIA symptoms and b presence of baseline depressive symptoms

Fig. 5

Change from baseline in YMRS Total score by treatment group in BD-I mania. *p < 0.05, **p < 0.01, ***p < 0.001 versus placebo, t test. Anxiety was defined as a PANSS anxiety item score of ≥3 at baseline. Irritability was defined as a YMRS irritability item score of
≥4 at baseline. Agitation was defined as a YMRS increased motor activity–energy item score of ≥3 at baseline. Severe AIA was defined as meeting the above criteria for all three AIA symptoms. Patients missing a value for the corresponding symptom at baseline were not included in the analysis. AIA, anxiety, irritability, and agitation; BD-I, bipolar I disorder; PANSS, Positive and Negative Syndrome Scale; SE, standard error; YMRS, Young Mania Rating Scale. a Patients with anxiety at baseline, b patients without anxiety at baseline, and c patients with severe AIA at baseline