Lurasidone for major depressive disorder with mixed features and irritability: a post-hoc analysis

Objective The aim of this post-hoc analysis was to evaluate the efficacy of lurasidone in treating major depressive disorder (MDD) with mixed features including irritability. Methods The data in this analysis were derived from a study of patients meeting DSM–IV–TR criteria for unipolar MDD, with a Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≥26, presenting with two or three protocol-defined manic symptoms, and who were randomized to 6 weeks of double-blind treatment with either lurasidone 20–60 mg/d (n=109) or placebo (n=100). We defined “irritability” as a score ≥2 on both the Young Mania Rating Scale (YMRS) irritability item (#5) and the disruptive-aggressive item (#9). Endpoint change in the MADRS and YMRS items 5 and 9 were analyzed using a mixed model for repeated measures for patients with and without irritability. Results Some 20.7% of patients met the criteria for irritability. Treatment with lurasidone was associated with a significant week 6 change vs. placebo in MADRS score in both patients with (–22.6 vs. –9.5, p<0.0001, effect size [ES]=1.4) and without (–19.9 vs. –13.8, p<0.0001, ES=0.7) irritability. In patients with irritable features, treatment with lurasidone was associated with significant week 6 changes vs. placebo in both the YMRS irritability item (–1.4 vs. –0.3, p=0.0012, ES=1.0) and the YMRS disruptive-aggressive item (–1.0 vs. –0.3, p=0.0002, ES=1.2). Conclusions In our post-hoc analysis of a randomized, placebo-controlled, 6-week trial, treatment with lurasidone significantly improved depressive symptoms in MDD patients with mixed features including irritability. In addition, irritability symptoms significantly improved in patients treated with lurasidone.


Introduction
Irritability frequently occurs in patients with a diagnosis of major depressive disorder (MDD), with prevalence estimates ranging from 35 to 55%. [1][2][3][4][5][6][7] As noted in the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5), 8 many individuals with a diagnosis of MDD report or exhibit irritability. However, irritability is not included in the core diagnostic criteria for MDD, nor is it evaluated as a symptom domain in many of the most widely used scales that measure depression severity (e.g., the Montgomery-Åsberg Depression Rating Scale [MADRS], the Hamilton Rating Scale for Depression [HAM-D], the Quick Inventory of Depressive Symptomatology-Self-Report [QIDS-SR 16 ], and the Patient Health Questionnaire-9 ).
The presence of irritability in MDD is associated with younger age of onset, increased chronicity and severity, greater impairment in functioning and quality of life, and higher levels of comorbidity-most notably anxiety, impulsivity, and substance use disorders. 2,3,[5][6][7]9 Some 3,10 but not all 6,7 studies of MDD have identified irritability as a risk factor for the development of a bipolar or bipolar mixed diagnosis.
The presence of irritable features-as part of a spectrum that may include anger, hostility, agitation, and aggressive behavior-has been found to be associated with a significantly delayed or reduced response to standard antidepressants in both unipolar MDD 6,[11][12][13] and bipolar depression. 14,15 MDD with mixed features is a common and often severe subtype of major depression that is recognized by the mixed-features specifier in DSM-5. 8 Prevalence estimates from clinical populations indicate that mixed features occur in at least 25% of patients with MDD. 11,14,[16][17][18][19][20][21][22] Irritability is not included as a criterion for mixed features in DSM-5, in part due to concerns regarding specificity. 8 Despite the prevalence and prognostic significance of irritability in MDD (with or without mixed features), few prospective studies have examined treatment response in this important clinical population.
Lurasidone is an atypical antipsychotic agent with high affinity for dopamine D 2 (K i = 1 nM) as well as for serotonin 5-HT 2A (K i = 0.5 nM) and 5-HT 7 (K i = 0.5 nM) receptors, 23 and moderate affinity for the 5-HT 1A receptor (K i = 6.8 nM). Lurasidone has demonstrated efficacy in acute and long-term treatment of schizophrenia, [24][25][26] as well as in treatment of bipolar depression, both as monotherapy and as an adjunctive therapy with lithium or valproate. 27,28 The purpose of the present post-hoc analysis was to assess the efficacy of lurasidone in treating MDD patients with mixed features presenting with irritability.

Methods
The data utilized in our post-hoc analysis were derived from a study designed to evaluate the efficacy of lurasidone for the treatment of patients with MDD presenting with subthreshold hypomanic symptoms (mixed features). The design of the original study is described in detail elsewhere. 29 In summary, this was a randomized, double-blind, placebo-controlled, 6-week trial that enrolled a total of 209 patients at 18 sites in the United States and 26 sites in Europe. Patients assigned to lurasidone received once-daily flexible dosing in the range of 20 to 60 mg/day. Diagnosis of MDD was confirmed with the Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Clinical Trials Version (SCID-CT), modified to record the presence of mixed symptoms. 30 Patients were required to have a score ≥26 on the MADRS 31 at both the screening and baseline visits. In addition, patients were required to have on most days, for at least two weeks prior to screening, two or three of the following manic symptoms: elevated or expansive mood, inflated self-esteem or grandiosity, more talkative than usual or feel pressure to keep talking, flight of ideas or racing thoughts, increased energy, increased or excessive involvement in activities with a high potential for negative consequences, and decreased need for sleep. Patients presenting with irritability, distractibility, and psychomotor agitation could be enrolled. However, consistent with the DSM-5 mixed-features specifier, these nonspecific symptoms were not included in the list of eligible manic symptoms required for study entry.
Our study was approved by an institutional review board at each investigational site and was conducted in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use's Good Clinical Practice Guidelines, and adhered to the ethical principles of the Declaration of Helsinki. An independent data and safety monitoring board reviewed and monitored patient data throughout the study.

Efficacy assessments
Efficacy assessment tools included the MADRS, 31 the Clinical Global Impressions-Severity scale (CGI-S) (which rates overall illness severity on a 7-point scale), 32 the Hamilton Rating Scale for Anxiety (HAM-A), and the Young Mania Rating Scale (YMRS). 33 Severity of irritable features was assessed using YMRS items 5 (irritability) and 9 (disruptive-aggressive behavior).

Irritable features subgroup
Patients were included in the irritable features group if their severity scores were ≥2 on both YMRS items 5 (irritability) and 9 (disruptive-aggressive behavior) at baseline. To further evaluate the prevalence of irritable features at baseline, three secondary definitions of irritability were also utilized: a YMRS item 5 score ≥2 at baseline, a YMRS item 9 score ≥2 at baseline, and the presence of irritability based on the modified SCID-CT administered at the screening visit (without applying YRMS severity criteria).

Statistical analysis
Efficacy endpoints were assessed for the patients meeting (and not meeting) criteria for irritable features using a mixed model for repeated measures (MMRM) analysis including fixed effects for treatment, visit, irritability subgroup, and pooled center; baseline score as a covariate; and treatment-by-visit, treatmentby-subgroup, subgroup-by-visit, and treatment-by-subgroup-by-visit interaction terms. An unstructured covariance matrix was employed for within-patient correlation. Analysis of efficacy endpoints was not corrected for multiplicity since they were done post hoc. Effect sizes (Cohen's d) were calculated as the least squares mean difference in the change score divided by the pooled standard deviation. Treatment response was defined as a ≥50% reduction from baseline to week 6 in MADRS score, and remission was defined as a week 6 MADRS score ≤12.

Baseline characteristics
A total of 43 patients (20.7%) had irritable features based on the presence of both YMRS items 5 (irritability) and 9 (disruptive-aggressive behavior) criteria at study baseline; 134 (64.4%) had irritable features based on the presence of the YMRS item 5 (irritability) criterion; 47 (22.6%) had irritable features based on the presence of the YMRS item 9 (disruptive-aggressive behavior) criterion; and 118 (56.7%) had irritable features based on a modified SCID-CT assessment.
Baseline demographic and clinical characteristicsincluding baseline MADRS, CGI-S, and HAM-A scores-were similar for patients with and without irritable features (based on the presence of both YMRS items 5 and 9 severity criteria) ( Table 1). For patients with irritable features, the mean YMRS item 5 (irritability) severity score was 3.4 at baseline (39.5% with a score ≥4), and the mean YMRS item 9 (disruptiveaggressive) severity score was 2.6 at baseline (18.6% with a score ≥4).
The mean daily dose of lurasidone was 33.0 mg in patients with irritable features and 37.1 mg in patients without irritable features. Completion rates for patients with irritable features treated with lurasidone and placebo were 91.3 and 81.8%, respectively, and completion rates in patients without irritable features were 94.2 vs. 86.3%, respectively.

Efficacy
Combined YMRS items 5 (irritability) and 9 (disruptive-aggressive behavior) criteria In patients with irritable features, based on the presence of both YMRS items 5 (irritability) and 9 (disruptiveaggressive behavior) criteria at study baseline, treatment with lurasidone was associated with significantly greater improvement at the week 6 endpoint compared to placebo on MADRS and YMRS scores ( Table 2) and on CGI-S score ( Figure 1A). Effect sizes for week 6 change in MADRS, YMRS, and CGI-S ranged from 1.2 to 1.4 for patients with irritable features. Significant improvement in MADRS score on lurasidone occurred at week 2 and at all subsequent study visits ( Figure 2).
In order to evaluate the potential effect of baseline anxiety severity on week 6 improvement in depressive    symptoms, we included baseline HAM-A total score as a covariate in the MMRM model analyzing change from baseline in MADRS score. In patients with irritable features, treatment effect sizes at week 6 were the same (Cohen's d = 1.4) regardless of whether anxiety severity was included as a covariate.
In patients with irritable features, based on the presence of the YMRS item 5 (irritability) criterion, treatment with lurasidone was associated with significant  improvement at week 6 endpoint compared to placebo (ES = 1.0); and in patients with irritable features, based on the presence of the YMRS item 9 (disruptiveaggressive behavior) criterion, treatment with lurasidone was associated with significant improvement at the week 6 endpoint compared to placebo (ES = 1.2; Figure 1B). In the total intention-to-treat (ITT) sample, endpoint improvement on lurasidone was significantly greater than placebo on the item 5 irritability score (-1.1 vs. -0.6, p = 0.004), but not on the item 9 disruptive-aggressive behavior score (-0.45 vs. -0.32, p = 0.13).

YMRS item 5 criterion
In patients with irritable features based on the presence of the YMRS item 5 (irritability) criterion, treatment with lurasidone was associated with significantly greater week 6 improvement compared to placebo on MADRS (-20.6 vs.

Tolerability
In patients with irritable features, defined utilizing combined YMRS items 5 and 9 severity criteria, treatment with lurasidone and placebo was associated with the following: rates of all-cause discontinuation: 8.7 vs. 18.2%, respectively; and discontinuation due to adverse events was 4.3 vs. 0%, respectively. In patients without irritable features, treatment with lurasidone and placebo was associated with the following: rates of allcause discontinuation = 5.8 vs. 13.8%, respectively; and discontinuation due to adverse events = 2.3 vs. 6.3%, respectively.

Discussion
MDD with mixed features is a common, severe, and poor prognosis subtype of depression. 8,17,20,21,34,35 The presence of irritability complicates the clinical picture of MDD with mixed features and may further increase treatment resistance to standard antidepressants. 6,[11][12][13][14][15] In the first prospective placebo-controlled trial in MDD with subthreshold hypomania (mixed features), lurasidone demonstrated significant efficacy in improving the symptoms of depression and subthreshold hypomanic symptoms. 29 The post-hoc analysis reported here now extends these results by finding lurasidone to have significant efficacy in MDD with mixed features patients who also presented with irritability (defined by the attainment of threshold scores on two irritability-related YMRS items).
Significant improvement in depressive and manic symptoms on lurasidone was observed in patients with irritable features, with notably larger treatment effect sizes for patients with (vs. without) irritability on the MADRS (1.4 vs. 0.7), the CGI-S (1.2 vs. 0.4), and the YMRS (1.2 vs. 0.5). Consistent with these findings, response and remission rates were larger in lurasidonetreated patients with (vs. without) irritable features (response NNT = 3 vs. 4; remission NNT = 4 vs. 5). Similarly significant improvement was also observed across these efficacy measures in patients with irritability defined using the single YMRS irritability item.
Treatment with lurasidone also significantly improved both irritability (as measured by YMRS item 5) and disruptive-aggressive behavior (as measured by YMRS item 9), with large effect sizes of 1.0 and 1.2, respectively.
These findings are in contrast to previous studies in populations with MDD which reported that the presence of irritable features may be associated with reduced response to standard antidepressants. 6,11,13,14 It is not clear why the magnitude of the lurasidone treatment effect observed in the current study was larger among patients with irritable features. Larger MADRS effect sizes appeared to be attributable, in part, to reduced improvement on placebo among patients with (vs. without) irritability (MADRS change = -9.5 vs. -13.8, respectively), while improvement on lurasidone was somewhat higher among patients with (vs. without) irritability (MADRS change = -22.6 vs. -19.9, respectively). Reduced placebo response in patients with irritable features also appeared to contribute to the larger treatment effect sizes observed for lurasidone on both the CGI-S and YMRS.
Previous studies of MDD have noted higher levels of anxiety in patients presenting with mixed features when compared to MDD patients without mixed features. 20,21 Mean baseline HAM-A scores in the current MDD-mixed population were relatively high (HAM-A = 17.0). Anxiety severity at baseline was slightly higher in the group with irritability (18.4) compared to the group without irritability (16.5). Controlling for baseline anxiety severity as a covariate in the MMRM model of MADRS change did not alter the week 6 effect size with lurasidone. The relationship between irritability and anxiety symptoms in mixedfeatures patients with MDD warrants further study, in part, to better understand the prognostic and treatment implications of their co-occurrence.
The mechanism for the beneficial effects of lurasidone in this MDD with mixed features and irritability patient population is not known. Preliminary studies have not reported significant efficacy for aripiprazole 13 or iloperidone 36 in the treatment of MDD presenting with irritability/anger (but without mixed features). In contrast, treatment with brexpiprazole, administered in combination with a standard antidepressant in an openlabel pilot study, 37 was found to improve both symptoms of depression and irritability in patients with irritable MDD, but without mixed features. Taken together, these reports suggest that not all atypical antipsychotic agents have efficacy in MDD patients presenting with irritability.
The results of the current analyses provide preliminary evidence suggesting that lurasidone, due to its demonstrated antidepressant effects, combined with its moodstabilizing properties, may be an important therapeutic option for the treatment of patients with MDD who present with subthreshold hypomanic (mixed) features including irritability.
Discontinuation rates (all-cause and due to adverse events) associated with lurasidone treatment tended to be higher in the irritability (vs. non-irritability) group. However, all-cause discontinuation rates on lurasidone were markedly lower than placebo in both groups. Rates of discontinuation due to adverse events were higher than placebo for the irritability group, but not for the non-irritability group. The number of treatmentemergent adverse events with an incidence ≥5% was low in both the irritability (nausea, abdominal discomfort) and non-irritability (insomnia, headache, nausea) subgroups, and the rates for these adverse events were all <10% and similar to placebo. Overall, the presence of irritability did not markedly influence the tolerability of lurasidone, but the agent was associated with a modest increased risk of study discontinuation due to adverse events.
The analysis reported here has several limitations. Post-hoc analyses are exploratory in nature and require prospective trials for confirmation of findings. The severity threshold used to define irritable features (based on YMRS item scores) may have been too low, resulting in the possible inclusion of some patients without clinically meaningful irritability. Furthermore, a validated scale was not utilized to assess the full spectrum of irritability/hostility/agitation symptoms and behaviors. A related concern is the lack of consensus regarding what constitutes irritability in terms of clinical presentation. It is not clear which subjective symptoms and feelings (e.g., irritability, annoyance, hostility, resentfulness) or outwardly observed behaviors (e.g., agitation, and hot-tempered, angry, or aggressive behavior) should be included in the construct. It is notable that several of the most widely used assessment measures in MDD clinical trials (e.g., the MADRS, the HAM-D, and the QIDS-SR 16 ) do not even include irritability as an item. The relative lack of valid and reliable scales to measure the presence and severity of irritability has been an impediment to research investigating the prevalence of irritability in MDD, its clinical impact, and the effectiveness of treatment, which in turn has encouraged reliance on items from scales validated for other purposes. 13,[36][37][38] Conclusions In this post-hoc analysis of a randomized, placebocontrolled, 6-week trial, treatment with lurasidone significantly improved depressive symptoms in patients with MDD with subthreshold hypomanic (mixed) features and irritability. Irritability and disruptive-aggressive symptoms also showed significant improvement. The magnitude of improvement in both depressive and irritable/aggressive symptoms suggests that lurasidone may be a useful treatment for this MDD mixed-features subpopulation, which is associated with high levels of chronicity, severity, and treatment resistance.