Effect of asenapine on manic and depressive symptoms in bipolar i patients with mixed episodes: results from post hoc analyses

Статьи Опубликовано в журнале:
«JOURNAL OF AFFECTIVE DISORDERS»; № 145; 2013; стр. 62-69.

J.M. Azorin^a,*, C. Sapin^b, E. Weiller^c

Abstract
Background: The efficacy of agents useful for mania is largely unproven in patients with mixed episodes.
Methods: The efficacy of asenapine in the treatment of mixed episodes was assessed using post hoc analyses on pooled data from two identically designed 3-week, randomized, double-blind, flexible dose, placebo- and olanzapine-controlled trials and their 9-week, double-blind olanzapine-controlled extension study. Efficacy was measured by changes on Young Mania Rating Scale (YMRS) and Montgomery-Asberg Depression Rating Scale (MADRS) total scores, and was analysed through analysis of covariance on observed cases of the intent-to-treat dataset.
Results: In the intent-to-treat population, 295 patients had a DSM-IV-TR mixed episode (placebo: 66; olanzapine: 122; asenapine: 107) in the 3-week trials. Of these, 102 patients (olanzapine: 56; asenapine: 46) entered the 9-week extension study.
At week 3, decreases in YMRS and MADRS total scores, were significantly (p < 0.01) greater with asenapine (YMRS: -15.0; MADRS: - 8.2) versus placebo (YMRS: - 11.5;MADRS: - 4.5); olanzapine did not separate from placebo (YMRS: -13.3; MADRS: -6.5). At week 12, further decreases in YMRS and MADRS total scores were observed with asenapine (YMRS: -22.4; MADRS: -11.9); non-statistically different from olanzapine (YMRS: -20.2; MADRS: -7.9).
Limitations: Results are from post hoc analyses of trials that were not designed to specifically evaluate mixed episodes.
Conclusions: These exploratory analyses provide supportive evidence for the efficacy of asenapine in treating the associated symptoms of mania and depression in bipolar I patients with mixed episodes.
Key words: Bipolar I disorder; Mixed episodes; Asenapine; Olanzapine; Remission

1. Introduction
The concept of mixed states is old, predating that of bipolar disorder itself (Swann, 2011). Various definitions have been and are still being proposed, but the concept always refers to a combination of depressive and manic features in the same episode. The DSM-IV-TR criteria require that patients have both full syndromal mania and depression. Depending on the definition, there is a wide range of reported rates of mixed states in the literature; from 5% to 75% (Hantouche et al., 2006). Mixed episodes represent a severe presentation of bipolar disorder. Mixed patients are characterized by an earlier appearance of bipolar symptoms, a higher risk of suicide, a higher occurrence of manic and depressive episodes, higher rates of rapid cycling, and more co-morbidities related to substance abuse and dependence, as well as anxiety disorders (Azorin et al., 2009; Swann, 2011).

The treatment of mixed states is made difficult by the fact that the efficacy of drugs shown useful for pure manias is largely unproven in the subset of patients with mixed episodes (Stahl et al., 2010).

Usually the magnitude of response to manic symptoms' treatment exceeds that of depression symptoms. Valproate and carbamazepine have shown some effectiveness, but the efficacy of lithium appears questionable. A small number of atypical antipsychotics were found to improve both manic and depressive symptoms, used as monotherapy or in combination to mood stabilizers (Fountoulakis et al., 2012).

Asenapine has been shown to be effective in the treatment of patients with manic or mixed episodes associated with bipolar I disorder, in two companion randomized, double-blind, placebo -and olanzapine-controlled 3-week trials (McIntyre et al., 2009a; McIntyre et al., 2010). Across trials, reductions in Young Mania Rating Scale (YMRS) total score were significantly greater with asenapine and olanzapine compared with placebo. In a 9-week extension of these trials (McIntyre et al., 2009b), asenapine met the criteria for non-inferiority to olanzapine. The effect of asenapine on depressive symptoms in subgroups of patients who participated in the same 3-week lead-in trials, but experienced clinically relevant depressive symptoms, was assessed by Szegedi et al. (2011). Three populations were selected: (1) Montgomery-Asberg Depression Rating scale (MADRS) total score ? 20; (2) Clinical Global Impression for Bipolar Disorder-Depression (CGI-BP-D) scale severity score ? 4; (3) diagnosis of mixed episode according to DSM-IV-TR. The decreases in MADRS total scores were found to be statistically greater with asenapine versus placebo at days 7 and 21 in all populations, whereas differences between olanzapine and placebo were not significant. In conclusion, the authors state the need for randomized controlled studies of asenapine in patients with bipolar depression to confirm the generalizability of their findings.

Nonetheless, there is still a lack of data on the efficacy of asenapine in mixed patients in the studies that have been conducted so far. For example, changes in YMRS scores in the specific population of DSM-IV-TR mixed patients were analyzed in only one of the two short-term trials (McIntyre et al., 2009a), response and remission rates were defined as percentage improvement on the YMRS only and threshold scores on YMRS were missing in both trials for the subpopulation of mixed patients. Data for this subpopulation were also completely absent in the 9-week extension study. In the analyses carried out by Szegedi et al. (2011), the efficacy of asenapine on manic symptoms and response rates based on percent improvement on the MADRS in the population of mixed patients were not assessed, neither was the tolerability of asenapine assessed. The latter may be worth considering as side effects such as extrapyramidal (Goodwin, 2009) or metabolic symptoms (Fagiolini et al., 2005) may worsen depressive features in bipolar patients.

Moreover, before implementing randomized controlled studies of asenapine in bipolar depression, it may be of interest to get some signal as to whether the efficacy of asenapine on depressive symptomatology is driven by its impact on the core features of depression.

The objective of these post hoc analyses is to try to yield further information on those missing data in order to better evaluate the efficacy and tolerability of asenapine in the treatment of manic and depressive symptoms in a cohort of patients with mixed episode defined according to DSM-IV-TR criteria.

2. Methods
These post hoc analyses include data from two identically designed 3-week, randomized, double-blind, flexible dose, placebo-and olanzapine-controlled trials (NCT00159744; NCT00159796) and their 9-week, double-blind olanzapine-controlled extension study (NCT00143182).

Each study was conducted in compliance with the Declaration of Helsinki, the principles of Good Clinical Practice and was approved by the appropriate institutional review boards. All enrolled patients provided written informed consent at the start of both the 3-week trials and the extension study.

2.1. Study designs and patient populations
The study designs and patient populations have been previously described (McIntyre et al., 2009a; McIntyre et al., 2009b; McIntyre et al., 2010). Briefly, the trials were conducted in 10 countries (Bulgaria, India, Malaysia, the Philippines, Romania, Russia, South Korea, Turkey, Ukraine, and the United States). The 3-week trials included adult patients with a current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised (DSM-IV-TR) diagnosis of manic or mixed episodes associated with bipolar I disorder, assessed using the Mini International Neuropsychiatric Interview (Sheehan et al.,1998), and a YMRS (Young et al., 1978) total score of at least 20 at screening and baseline, a current episode that began less than 3 months before screening, and a documented history of at least 1 moderate to severe manic or mixed episode, with or without psychotic features. Patients who completed one of the 3-week trials, regardless of clinical status, were eligible for the 9-week extension study, if they had no major protocol violations, and if the investigator judged that continued treatment could be of clinical benefit. Principal exclusion criteria in both the lead-in and extension studies were a primary diagnosis other than bipolar I disorder, a rapid-cycling mood course, substance abuse or dependence, or being at imminent risk of harm to self or others.

To allow for washout of medications whose use was not permitted during the trial, a single-blind placebo run-in period of up to 7 day preceded randomization. Limited doses of specific benzodiazepines and non-benzodiazepine sedative-hypnotics were allowed during treatment week 1 of the 3-week trials. All other psychotropic medications were prohibited in the lead-in and extension studies (McIntyre et al., 2009a; McIntyre et al., 2009b; McIntyre et al., 2010).

2.2. Treatment
After single-blind placebo run-in periods of up to 7 day in the lead-in studies, patients were randomized to 3 weeks of asenapine (20 mg on day 1, dose divided morning and evening; flexible-dose 20 or 10 mg daily thereafter), placebo, or olanzapine (15 mg on day 1, flexible-dose 5-20 mg daily thereafter) in a 2:1:2 ratio (McIntyre et al., 2009a; McIntyre et al., 2010). In the extension study, patients who had received active treatment with asenapine or olanzapine in the 3-week trials continued the same double-blind regimen (McIntyre et al., 2009b). Patients who had received placebo in the 3-week trials were blindly randomised to asenapine (20 mg or 10 mg daily, dose divided morning and evening), and, as with the original studies, they are not included in the present analyses to avoid bias due to differences in exposure.

These post hoc analyses were conducted on the pooled 3-week data of the subset of patients diagnosed with a mixed episode according to DSM-IV-TR, and complemented by the data collected during the 9-week extension trial.

2.3. Assessments
The effect of treatment on manic symptoms was evaluated by the change from baseline to week 3 (day 21) and to week 12 (day 84) in the YMRS total score and for each individual item score.

The effect of treatment on depressive symptoms was evaluated by the change from baseline to week 3 (day 21) and to week 12 (day 84) in the MADRS (Montgomery, 1979) total score and for each individual single item score. Composite response, defined as ? 50% reduction from baseline in YMRS and MADRS scores, and composite remission, defined as YMRS ?12 and MADRS ?10, were also analysed.

Safety was evaluated on the basis of treatment emergent adverse events, potentially clinically significant weight changes ( ? 7% gain or loss) and changes in metabolic parameters.

Treatment-emergent adverse events (hereafter referred to as adverse events) included any adverse events observed by the investigator or reported spontaneously by the patient during the treatment period. These were classified according to Medical Dictionary for Regulatory Activities (MedDRA) version 8.1. As with the original studies (McIntyre et al., 2009a; McIntyre et al., 2009b; McIntyre et al., 2010), we report AEs that occurred in ? 5% of patients treated and that occurred at twice the frequency of placebo. Weight and metabolic parameters (fasting triglycerides, fasting glucose, total cholesterol, high-density lipoproteins (HDL), and low-density lipoproteins (LDL)) were assessed at baseline and study endpoint (day 21).

2.4. Statistical analysis
These post hoc efficacy and safety analyses were based on the intent-to-treat (ITT) dataset, which comprised all randomised patients who took at least one dose of study medication and had at least one valid post-baseline YMRS assessment.

Changes in YMRS and MADRS scores were analysed through analysis of covariance on observed cases with treatment and pooled centre as factors and baseline value as covariate. The treatment-by-study interaction was not considered in the final models since it was not statistically significant at the 0.10 level. Treatment effect on composite response and remission were analysed with Chi-square tests.

All statistical tests are two-sided with statistical significance set to 0.05. Between-treatment group differences are displayed using least-square (LS) means with standard errors (SE). No adjustments were made for multiple comparisons. All statistical analyses were performed using SAS version 9.2.

3. Results
3.1. Disposition and demographics

The intent-to-treat population for these post hoc analyses consisted of 295 bipolar I patients experiencing mixed episodes: asenapine, n = 107, olanzapine, n= 122 and placebo, n=66 (Fig. 1). Of these, 102 patients entered the 9-week extension study: asenapine, n=46 and olanzapine, n = 56. The lead-in trials were completed by 63%, 75%, and 65% of asenapine-, olanzapine-, and placebo-treated mixed episode patients, respectively (p=0.093).

Fig. 1. CONSORT diagram of patients with mixed episodes participating in the two 3-week lead-in and 9-week extensions studies.

The completion rate in the extension study was 50% for asenapine and 59% in the olanzapine group. Reasons for discontinuation in each treatment group are displayed in Fig. 1. These completion rates were consistent with the overall population in the pivotal studies. Table 1 presents the patient disposition, demographics, mean baseline YMRS and MADRS total score and mean daily dose for the two lead-in studies and the extension study.

Table 1

Clinical characteristics, and disposition at baseline for patients experiencing mixed episodes participating in (A) the two 3-week trials and (B) 9-week double-blind extension study.

A.	Asenapine	Olanzapine	Placebo
IIT population, n	107	122	66
Sex, male, n (%)	61 (57.0)	70 (57.4)	30 (45.5)
Age, years (mean±SD)	38.2 ± 11.3	38.7 ± 10.5	39.4 ± 12.6
YMRS total score, (mean±SD)	27.8 ± 5.8	27.6 ± 6.4	27.6 ± 6.2
MADRS total score, (mean±SD)	16.8 ± 6.4	16.7 ± 6.9	19.0 ± 7.2
Age at first diagnosis, years (mean ± SD)	27.0 ± 10.4	28.7 ± 11.1	28.6 ± 13.3
Duration of bipolar symptoms, years (mean±SD)	11.7 ± 9.3	10.5 ± 9.0	11.4 ± 9.3
Number of previous manic episodes 12 months prior inclusion (mean±SD)	1.0± 0.6	1.1 ± 0.7	1.2 ± 0.6
Lifetime (mean±SD)	9.9 ± 9.8	9.8 ± 13.5	11.9 ± 9.2
Number of previous depressive episodes 12 months prior inclusion (mean±SD)	0.7 ± 0.7	0.7 ± 0.6	0.6 ± 0.6
Lifetime (mean±SD)	6.3 ± 7.2	8.9 ± 14.1	9.2 ± 8.6
Daily dose, mg (mean±SD)	18.4 ± 2.7	15.6 ± 2.3	-
B.	Asenapine	Olanzapine
IIT population, n Sex, male, n (%) Age, years (mean±SD) Daily dose, mg (mean±SD)	46 22 (47.8) 39.6 ± 12.2 17.2 ± 4.0	56 32 (57.1) 39.3 ± 11.5 16.1 ± 2.5

In the 3-week trials, the baseline demographic characteristics were comparable across treatment groups (Table 1A). Men comprised a slight majority in the asenapine and olanzapine groups (57%) and women comprised a slight majority in the placebo group (54%). The mean age was between 38 and 39 years. The YMRS and MADRS total scores at baseline were comparable between treatment groups (Table 1). The most common reasons for discontinuation were adverse events and withdrawn consent in the asenapine group, lack of efficacy and withdrawn consent in the olanzapine treated patients, and lack of efficacy and withdrawn consent in the placebo group (Fig. 1).

In the 9-week double-blind extension study the baseline demographic characteristics were comparable between treatment groups (Table 1). Women comprised of a slight majority in the asenapine group (52%) and men comprised of a slight majority of men in the olanzapine group (57%) and the mean age was 39 years in both treatment groups.

3.2. Effect on manic symptoms (YMRS)

The change (LS mean ± SE) in YMRS total score from baseline to week 3 were significantly greater (p=0.015) with asenapine (-15.0 ± 0.9) compared to placebo (-11.5 ± 1.2). The difference between olanzapine and placebo were not statistically different (p=0.169) on the mean YMRS total score change from baseline to week 3 (-13.3 ± 0.9) (Fig. 2). Of the 11 items in the YMRS, asenapine was statistically significantly (p < 0.05) superior to placebo in reducing the YMRS individual item scores for ''elevated mood'' (-1.13 versus - 0.69, p=0.021), ''sexual interest'' (-0.64 versus -0.25, p=0.039) and ''language/thought disorder'' (-1.10 versus -0.77, p=0.040) between baseline and week 3.

Fig. 2. Changes in YMRS total from baseline to weeks 3 and 12 in patients experiencing mixed episodes. * active treatment versus placebo: p < 0.05.

The effect of asenapine on manic symptoms was maintained over the extension trial. By week 12, the reduction from baseline was greater for asenapine than for olanzapine (-22.4± 1.8 versus - 20.2 ± 1.2) though not statistically significant (p=0.271, Fig. 2).

3.3. Effect on depressive symptoms (MADRS)
Asenapine was statistically significantly superior to placebo in terms of mean change from baseline in MADRS total score at week 3 (- 8.2 ± 0.9 versus -4.5 ± 1.2, respectively; p=0.009) (Fig. 3A). The difference between olanzapine and placebo was not statistically significant (p=0.181) at week 3 (- 6.5 ± 0.8).

The effect of asenapine on depressive symptoms was maintained over the extension trial. By week 12, the mean change from baseline in MADRS total score was greater than that for olanzapine (-11.9 ± 2.6 versus - 7.9 ± 1.8) though not statistically significant (p=0.138) (Fig. 3A).

Of the 10 items in the MADRS, at week 3 asenapine was significantly superior to placebo in reducing the individual item scores for ''inner tension'' (-1.25 versus - 0.66, p=0.011), ''reduced appetite'' (-0.55 versus - 0.27, p=0.050), and ''inability to feel'' (-0.75 versus -0.29, p=0.028) between baseline and week 3. At week 3, asenapine was significantly superior to olanzapine in reducing the MADRS item score for ''inner tension'' (-1.25 versus - 0.82, p=0.025). Olanzapine did not separate from placebo in reducing any of the MADRS individual item scores although trends towards statistical significance were observed in favour of olanzapine for the item ''apparent sadness'' (Fig. 3B).

Fig. 3. Changes in (A) MADRS total score from baseline to weeks 3 and 12, and in (B) MADRS item scores from baseline to week 3 in bipolar I patients with mixed episodes.

3.4. Composite response and remission
The composite response (? 50% reduction from baseline in YMRS and MADRS scores) rate was significantly greater (p=0.023) with asenapine (46.3%) than with placebo (24.4%) at week 3; the difference between olanzapine (37.5%) and placebo was not statistically significant (p=0.141). The composite remission (YMRS ? 12 and MADRS ? 10) rate was statistically significantly greater (p=0.033) with asenapine (44.8%) than with placebo (24.4%) at week 3; the difference with olanzapine (35.2%) was not statistically significant (p=0.218).

The effect of asenapine on composite response and remission was maintained over the extension trial. By week 12, the composite response and remission rates were greater than that for olanzapine though not statistically significant (composite responders 57.1% versus 46.2%, p=0.741, composite remitters 50% versus 46%, p = 1.0) (Fig. 4).

Fig. 4. (A) Composite responders, % ( ? 50% reduction from baseline in YMRS and MADRS scores) and (B) composite remitters, % (YMRS ? 12 and MADRS ? 10), at weeks 3 and 12 in bipolar I patients experiencing mixed episodes.

3.5. Safety and tolerability
Safety for the entire population in these studies has been reported elsewhere (McIntyre et al., 2009a, 2009b, 2010). Here we describe the tolerability of this subgroup of patients in the 3-week trials diagnosed with a mixed episode according to DSM-IV-TR criteria. Adverse events were reported by 84.1% of asenapine-treated patients, by 69.7% of placebo patients, and by 73.8% of olanzapine-treated patients.

With asenapine, adverse events reported by ? 5% of patients and that occurred at twice the frequency of placebo (Table 2) were sedation (19.6% versus placebo 3%), somnolence (14% versus 3%), dizziness (11.2% versus 3%), increased appetite (6.5% versus 1.5%), increased weight (5.6% versus 0%) and oral hypoaesthesia (5.6% versus 0%). With olanzapine, adverse events reported by ? 5% of patients and that occurred at twice the frequency of placebo (Table 2) were sedation (18.9% versus placebo 3%), increased weight (13.1% versus 0%), dry mouth (13% versus 3%), somnolence (7.4% versus 3%) and dizziness (6.6% versus 3%).

Table 2

Adverse events with an incidence ?5% in any treatment group and twice the frequency of placebo.

	Asenapine (n=107)	Olanzapine (n=122)	Placebo (n=66)
Patients with ?1 adverse event, n(%)	90 (84.1)	90 (73.8)	46 (69.7)
Sedation, n(%)	21 (19.6)	23 (18.9)	2 (3.0)
Somnolence, n(%)	15 (14.0)	9 (7.4)	2 (3.0)
Dizziness, n(%)	12 (11.2)	8 (6.6)	2 (3.0)
Increased appetite, n(%)	7 (6.5)	5 (4.1)	1 (1.5)
Weight increased, n(%)	6 (5.6)	16 (13.1)	0
Hypoaesthesia oral, n(%)	6 (5.6)	2 (1.6)	0
Dry mouth, n(%)	4 (3.7)	16 (13.1)	2 (3.0)
Fatigue, n(%)	4 (3.7)	7 (5.7)	1 (1.5)
Patients with ?1 extrapyramidal adverse event, n(%)	12 (11.2)	12 (9.8)	3 (4.5)
Akathisia, n(%)	7 (6.5)	7 (5.7)	2 (3.0)
Dyskinesia, n(%)	1 (0.9)	0	0
Dystonia, n(%)	2(1.9)	2 (1.6)	0
Parkinsonism, n(%)	1 (0.9)	0	0
Tremor, n(%)	6 (5.6)	5 (4.1)	1 (1.5)

The incidence of EPS-related adverse events was 11.2% with asenapine, 4.5% with placebo, and 9.8% with olanzapine (Table 2).

Increased weight was reported as an adverse event in 5.6% of the asenapine- and 13.1% of the olanzapine-treated patients. The incidence of potentially clinically significant weight gain (? 7% increase from baseline), was lower in the asenapine-treated patients (13.8%) compared to olanzapine treated patients (25.9%). In the placebo group there were no patients with potentially clinically significant weight gain (Table 3). Weight loss was also observed (1-2%) across all treatment groups (Table 3). Changes from baseline in metabolic parameters, were generally small and not considered clinically relevant (Table 4).

Table 3

Potentially clinical relevant weight changes.

	Asenapine	Olanzapine	Placebo
Clinical relevant weight changes
n	94	108	55
? 7% gain, n(%)	13 (13.8)	28 (25.9)	0 (0.0)
?7% loss, n(%)	1 (1.1)	2(1.9)	1 (1.8)

Table 4

Mean changes from baseline in serum lipids and fasting triglycerides and glucose.

	Asenapine		Olanzapineapine		Placebo
	n	Mean ( ± SD)	n	Mean ( ± SD)	n	Mean ( ± SD)
Triglycerides (fasting) (mmol/L)
Baseline	99	1.7 ( ± 1.22)	117	1.7 ( ± 1.01)	58	1.6 (± 0.64)
?Last assessment	64	0.17 (± 1.30)	81	0.4 (± 1.19)	44	0.04 (± 0.59)
Glucose (fasting) (mmol/L)
Baseline	40	5.0 (± 0.97)	54	5.2 (± 0.86)	28	5.6 (± 0.97)
?Last assessment	21	-0.22 ( ± 1.06)	36	0.15 (± 1.25)	24	-0.59 (± 1.01)
Total cholesterol (mmol/L)
Baseline	107	5.2 (± 1.2)	122	5.0 ( ± 1.1)	65	5.2 (± 1.29)
?Last assessment	92	0.04 (± 0.78)	102	0.43 (± 0.86)	56	0.05 (± 0.83)
High Density Lipoprotein (HDL) (mmol/L)
Baseline	107	1.4 ( ± 0.53)	122	1.3 (± 0.42)	65	1.3 (± 0.43)
?Last assessment	92	0.002 (± 0.23)	102	0.028 (± 0.28)	56	-0.003 (± 0.21)
Low Density Lipoprotein (LDL) (mmol/L)
Baseline	104	2.9 (± 0.99)	122	2.9 (± 0.90)	65	3.1 ( ± 1.0)
? Last assessment	84	0.06 (± 0.71)	96	0.3 (± 0.79)	56	0.1 (± 0.69)

4. Discussion
These post hoc analyses show the efficacy of asenapine in the treatment of symptoms associated with DSM IV-defined mixed episodes as measured by changes on the YMRS and MADRS total scores, or by composite responder or composite remission (that is, achieving response or remission on both the YMRS and MADRS). The efficacy of asenapine was found to be significantly greater than placebo at week 3. Szegedi et al. (2011) assessed the effect of asenapine on depressive symptoms in bipolar I disorder patients with manic or mixed episodes who participated in the same lead-in trials. Subgroup analyses were conducted in patients experiencing clinically relevant depressive symptoms at baseline defined either on the basis of a threshold score on the MADRS or the Clinical Global Impression for Bipolar Disorder-Depression (CGI-BP-D) or according to DSM-IV-TR mixed episode. In the present paper, the effect on depressive symptoms was further evaluated up to 12 weeks; in addition we also examined the effect of asenapine on manic symptoms in mixed patients. In the only short term trial in which the efficacy of asenapine on manic symptoms of DSM-IV-TR mixed episode patients was assessed, the superiority of asenapine over placebo failed to reach statistical significance on the change in YMRS score at day 21, due to the low number of patients in each treatment group and due to the high placebo response in this subgroup of patients. The results of our analyses are therefore the first to suggest the efficacy of asenapine on both manic and depressive symptoms in patients with a mixed episode. The findings of the present analyses are in line with those from previous studies indicating the potential usefulness of some atypical antipsychotics to treat both sets of mood symptoms in mixed patients (Nivoli et al., 2011).

In our analyses, olanzapine did not separate from placebo at week 3. This is particularly interesting with respect to the findings from a previous post hoc analysis showing that among patients with dysphoric mania (defined by a baseline Hamilton Depression Rating scale [HAM-D] score of > 20), olanzapine-treated patients showed greater improvement at week 3 than placebo-treated patients on both manic (YMRS) and depressive (HAM-D) symptom ratings (Baker et al., 2003). A recent review (Pompili et al., 2011) also concluded that both asenapine and olanzapine were efficacious in the treatment of mixed or manic episodes. When mixed episodes were analysed separately, we found that olanzapine did not separate from placebo.

As regards the effect on MADRS individual item scores, asenapine did significantly better than placebo on ''inability to feel'', ''reduced appetite'' and ''inner tension'', and significantly better than olanzapine on ''inner tension''. The effect on ''inability to feel'' is worth rating, because it is considered to be one of the most characteristic features of depression-related symptoms of mixed episodes, along with hopelessness and suicidal ideation, according to some authorities in the field (Swann, 2011). Hopelessness was not assessed in our study, and patients at risk of suicide were excluded from the trials.

While an effect on appetite is non-specific, this does not appear to be the case for ''inner tension''. According to Swann, ''inner tension'', as specified in the MADRS, may be a reflection of ill defined discomfort fuelled by the simultaneous presence of contradictory feelings of depression and elation, which results in mental turmoil mounting to panic, dread or anguish (Swann, 2011). In mixed episodes, inner tension may be expressed through agitation, and in the most severe cases, lead to suicidal behaviour (Swann, 2011).

Asenapine was generally as well tolerated in the mixed episode cohort as in the wider population (McIntyre et al., 2009a^,, 2009b^,, 2010). The adverse events reported in the mixed episode group were essentially the same as for the wider population. Sedation and somnolence were the most frequently reported adverse events. Nonetheless, it is worth mentioning that for patients with severe anxiety and intense agitation, especially those mixed patients who convey the highest risk of suicide, this adverse event may, in some cases, be of benefit, in clinical practice. As in the wider population (McIntyre et al., 2009a^,, 2009b^,, 2010), weight gain and metabolic disturbances were observed in some of the asenapine-treated patients in the mixed episode cohort, but to a lesser extent compared to olanzapine. These findings may be particularly relevant for this subpopulation which is at high suicidal risk, inasmuch as bipolar patients showing abdominal obesity and metabolic syndrome were found to be more likely to report a lifetime history of suicide attempts (Fagiolini et al., 2005).

The results of these post hoc analyses showing the efficacy of asenapine on depressive features of mixed patients are supported by in vitro and in vivo preclinical data. Antagonism of both serotonergic (5 HT2A, 5 HT2C, 5HT7) and adrenergic (?2) receptors are likely to be involved (Giorgetti and Tecott, 2004; Blier and Szabo, 2005; Guscott et al., 2005).

Moreover, asenapine was reported to attenuate chronic mild stress-induced ''anhedonia'', in animal models, which might be related to the effect we found on ''inability to feel'' in mixed patients (Marston et al., 2011).

The results of this study must be considered in the context of several limitations. First, our results are from post hoc analyses of trials that were not designed to specifically address mixed episodes and the results should be taken with that caveat. Second, these trials were not designed to compare the efficacy and tolerability of asenapine with that of olanzapine, so any comparisons in this regard should be made with caution. Third, the duration of these trials (even at 12 weeks) may be insufficient to adequately make clinical decisions regarding the efficacy and safety of long-term asenapine treatment in patients with bipolar disorder: in particular, effects of asenapine on weight gain and metabolic parameters should be interpreted with caution. Fourth, the patients' baseline YMRS scores were much higher than their MADRS scores, suggesting that our sample of mixed patients could be a sample of patients with dysphoric mania, thus our conclusions may not apply to patients with other types of mixed states. However, Szegedi et al. (2011) found comparable decreases in MADRS scores with asenapine in mixed patients showing higher levels of depressive symptoms as assessed by baseline MADRS scores. Finally, as a high number of comparisons were made, the statistical significance threshold p< 0.05 may not be ideal for the validity of the findings. However, due to the exploratory nature of our post hoc analyses, we were more interested in avoiding type II than type I errors. Furthermore, several of our most important findings, showed some plausibility, either psychopathological or biological.

To conclude, these exploratory post hoc analyses provide supportive evidence for the efficacy of asenapine in treating the associated symptoms of mania as well as core features of depression in bipolar I patients with mixed episodes. Further prospective studies in this specific population are warranted to confirm these preliminary findings. There is also a need for pragmatic studies to address efficiency of the drug in mixed patients with comorbid conditions and high suicidal risk.

Role of funding source
These analyses were supported by H. Lundbeck A/S (Copenhagen, Denmark). The studies used in these analyses were sponsored by Merck (Whitehouse Station, New Jersey, USA).

Conflict of interest
J-M Azorin receives, or has received, research support and has acted as a consultant and/or served on a speaker's bureau for Bristol-Myers Squibb, Janssen, Eli Lilly, Lundbeck, Novartis, Pfizer, Servier and Sanofi-Aventis.
C. Sapin and E. Weiller are employees of H. Lundbeck A/S.

Acknowledgements
J.K. Simonsen (H. Lundbeck A/S) provided support in the preparation, revision, and editing of the methods and results sections of the manuscript.

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