DR. AK KALA AWARD PAPER
Year : 2014 | Volume
: 19 | Issue : 2 | Page : 56--61
A comparative study of olanzapine versus asenapine in acute treatment of manic episode: A 3-week prospective study
Ajeet Sidana, Prannay Gulati, BS Chavan
Department of Psychiatry, Government Medical College and Hospital, Chandigarh, India
Correspondence Address:
Ajeet Sidana
Department of Psychiatry, 5th Level, D-Block, Government Medical College and Hospital, Sector 32, Chandigarh
India
Abstract
Introduction: Treatment of bipolar disorders has evolved over the years from conventional mood stabilizers to second-generation antipsychotics. Among the atypical antipsychotics, few have been approved by Food and Drug Administration as treatment of bipolar disorders. Aim: To study the efficacy and tolerability of olanzapine and asenapine in the acute treatment of bipolar disorder-manic episode in a 3-week randomized prospective study. Materials and Methods: A 3-week randomized, prospective, comparative, flexible doses of olanzapine (5-30 mg/day) and asenapine (10-20 mg/day) for acute treatment of bipolar disorder-current manic episode with or without psychotic symptoms in hospitalized patients. Results: The end-point reduction in mean score of Young Mania rating scale in the olanzapine group was 15.82 in comparison to 6.88 in the asenapine group. Mean score on clinical global impression for bipolar disorder and positive and negative syndrome scale was significantly less in the olanzapine group at the end of the study. 81.81% patients in olanzapine group and 17.60% patients in asenapine group had clinical response. There was significant average weight gain in the olanzapine group - 1.9 kg in comparison to 0.87 kg in asenapine group. Conclusion: The clinical response with olanzapine is significantly higher than the asenapine in the treatment of bipolar disorder-manic episode with or without psychotic symptoms. However, there is significant weight gain in olanzapine-treated patients.
How to cite this article:
Sidana A, Gulati P, Chavan B S. A comparative study of olanzapine versus asenapine in acute treatment of manic episode: A 3-week prospective study.J Mental Health Hum Behav 2014;19:56-61
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How to cite this URL:
Sidana A, Gulati P, Chavan B S. A comparative study of olanzapine versus asenapine in acute treatment of manic episode: A 3-week prospective study. J Mental Health Hum Behav [serial online] 2014 [cited 2023 Jun 4 ];19:56-61
Available from: https://www.jmhhb.org/text.asp?2014/19/2/56/153711 |
Full Text
Introduction
Bipolar disorder is a chronic disease that is characterized by recurrent episodes of mania and depression having lifetime prevalence of approximately 5.5%, with estimated prevalence of bipolar I disorder between 0.5% and 1.6%. [1] Bipolar I disorder is associated with high disability, morbidity, and mortality rates, and individuals often have co-morbid medical diseases that further contribute to its burden. [2],[3]
Mood stabilizers and antipsychotic drugs have been the mainstay of treatment of acute mania with and without psychotic features. Conventional mood stabilizers (e.g., lithium and divalproex) have traditionally been used as first-line agents for mania in bipolar I disorder. [4] However, second-generation antipsychotics are being prescribed more often as alternative monotherapies or as an adjunct treatment in bipolar disorder. [5] Olanzapine, risperidone, ziprasidone, aripiprazole, and quetiapine are the most widely used antipsychotics in the acute setting. Recently, asenapine has been approved by United States Food and Drug Administration in adults for acute treatment of manic or mixed episodes with or without psychotic features associated with bipolar I disorder and also, in the acute treatment of schizophrenia.
Side-effects most often associated with antipsychotic medications include somnolence, sedation, insomnia, dizziness, headaches, gastrointestinal symptoms, sexual dysfunction, and extrapyramidal symptoms (EPS). The metabolic and weight gain side-effects associated with antipsychotics may be the biggest contributors to nonadherence. [6],[7] Nonadherence to medications can result in severe symptoms and increased mood episodes, increased psychiatric hospitalizations, and suicidality. [8],[9],[10]
Olanzapine is an atypical antipsychotic with proven efficacy in the treatment of bipolar mania in the acute settings. [11],[12] However, it is associated with significant weight gain, somnolence, and other adverse events. In recently conducted trials, asenapine was found to be efficacious for manic, and mixed states in bipolar disorder compared with placebo control and compared equally well to olanzapine on efficacy measures after 3 weeks of treatment. [13],[14] Even in the extended treatment of patients experiencing manic symptoms associated with bipolar I disorder, asenapine was efficacious, showed noninferiority to olanzapine, and was well tolerated as suggested by less percentage of patients having significant weight gain and favorable changes in lipid profile and fasting blood sugar (FBS) levels while on asenapine when compared to olanzapine-treated patients. [15],[16] However, few of these studies were not designed to directly compare efficacy and tolerability between asenapine and olanzapine, and results were based on post-hoc analysis. [13],[14] Furthermore, to the best knowledge of the authors, there is no published study from India to date comparing the clinical efficacy and tolerability of asenapine and olanzapine. Hence, this study was done to compare the clinical efficacy and tolerability profile of these two drugs in the treatment of a manic episode.
Materials and Methods
Patients
Forty consecutive patients aged between 18 and 60 years with a diagnosis of bipolar disorder current manic episode, with or without psychotic features, as per International Classification of Diseases (ICD-10) [17] criteria, giving informed consent for the study, were enrolled. For inclusion into the study, a minimum total score of 20 on the Young Mania rating scale (YMRS) was required on the day of inclusion into the study (baseline). [18] Patients with associated serious and unstable medical illness, having concomitant use of any psychoactive substance, except nicotine and caffeine, within past 30 days fulfilling dependence criteria as per ICD-10, [17] adverse reaction and nonresponsive to olanzapine and asenapine in the past and patients who were on continuous medications such as lithium, anti-convulsants or antipsychotic medications at least for last 1 week were excluded from the study.
Study design
It was an open-label, randomized, comparative study. All the participating patients were admitted and randomly assigned to either Group 1 (olanzapine group) or Group 2 (asenapine group) and hospitalization was continued for the study period of 3 weeks. Patients in Group 1 received olanzapine and Group 2 received sublingual asenapine. Efforts were made to keep the dosages of medications in the therapeutic range, that is, olanzapine (5-30 mg/day) and asenapine (10-20 mg/day) and dose titration was done as per severity of the symptoms and tolerability.
Concomitant use of lorazepam was permitted, but only if the patient manifested with acute agitation and/or sleep disturbances severe enough to disrupt routine ward management. The symptom rating scales were administered at the fixed time in the morning. In the case of EPS, trihexyphenidyl up to a maximum dose of 6 mg/day, was permitted. However, prophylactic use of trihexyphenidyl was not allowed.
Assessments
Patients were assessed for the symptoms and the severity of illness with 11-item YMRS and the clinical global impression for bipolar illness disorder (CGI-BP) scale. [18],[19] The assessments using YMRS were done at the baseline, day 2, 4, week 1, week 2, week 3 and CGI-BP scale was applied at baseline, week 1, week 2 and week 3. The primary efficacy endpoint was change in YMRS total score from baseline to week 3. Secondary efficacy endpoints included the percentages of YMRS responders (patients demonstrating ≥50% YMRS total score reductions at endpoint) and YMRS remitters (patients with YMRS total scores ≤12 at endpoint). The positive and negative syndrome scale (PANSS) was used to assess changes in the psychotic symptoms. [20] In case there was ≤25% improvement in any of the patients at the end of the study (week 3), they were considered as nonresponder and managed as per the standard protocol in the department.
Safety profile of the drugs was assessed at week 1, 2, and 3 by monitoring adverse events using a checklist and scores on EPS rating scale (Simpson-Angus scale). [21] Monitoring of laboratory tests values (Hemogram, renal function tests, liver function tests, FBS, lipid profile), electrocardiography (ECG) changes, and changes in weight was also done at baseline, week 1, 2, and 3.
Statistical analysis
The statistical analysis included Chi-square test for qualitative data and Analysis of Variance for quantitative data. T-test was applied to compare individual assessments. Data was represented in mean and standard deviation and significance level was P < 0.05.
Results
A total of 40 patients, fulfilling the inclusion criteria were recruited in the study. Finally, we had 22 patients and 18 patients in olanzapine and asenapine groups, respectively. However, one patient from the asenapine group took premature discharge from the ward due to personal reasons before completion of the assessment period and was excluded from the study. Thus, the final analysis was done on 39 patients, 22 in the olanzapine group, and 17 in the asenapine group.
The two groups were comparable on sociodemographic variables, such as mean age, sex distribution, marital status, education, religion and family type and did not show any statistically significant difference [Table 1]. On the basis of diagnosis, patients were divided into bipolar disorder manic episode, with or without psychotic symptoms. Both the groups were comparable in distribution of patients and the difference was not statistically significant [Table 1]. The mean of the duration of the current episode was 24.65 days and 25.77 days in olanzapine and asenapine group respectively, and the difference was not statistically significant (P = 0.705).{Table 1}
Mean dose (in mg) in olanzapine and asenapine groups were 24.54 ± 5.22 and 18.75 ± 2.10, respectively. None of the patient from both the groups discontinued treatment due to adverse effects of the drugs. Lorazepam was required concomitantly in 82.35% of patients in the asenapine group with an average dose of 3.57 mg/day, whereas only 68.18% of olanzapine-treated patients required concomitant lorazepam with average dose of 3.13 mg/day. Trihexyphenidyl was used to treat EPS in five patients in the olanzapine group and four patients in the asenapine group and average dose was 2.4 mg and 3 mg, respectively.
Primary efficacy
The mean YMRS score at baseline in olanzapine and asenapine group were 28.47 and 29.68 respectively, and the difference between the groups was not significant (P = 0.49). Olanzapine group had lesser mean YMRS scores than asenapine group at week 2 and week 3 and the difference between the two groups in mean YMRS scores was significant at week 2 (P = 0.017) and week 3 (P = 0.001) [Figure 1]. The end-point reduction in mean score of YMRS in olanzapine group was 15.82 ± 1.56 in comparison to 6.88 ± 2.85 in asenapine group.{Figure 1}
On comparison of onset of improvement based on the basis of reduction in YMRS score, significant reduction was seen in olanzapine group from day 4 (P = 0.026) while in asenapine group, significant reduction was seen from day 7 (P = 0.031).
Secondary efficacy
Clinical global impression BP scores were comparable between the groups at baseline [Table 2]. However, the mean score in the olanzapine group at week 3 was significantly less than of asenapine group (P = 0.01).{Table 2}
Both the groups were comparable at baseline in severity of psychotic symptoms as assessed by PANSS total score [Table 2]. However, the olanzapine group had significantly more reduction in PANSS total score at week 2 (P = 0.007) and week 3 (P = 0.004) than asenapine group.
Response and remission
Clinical response, characterized as ≥50% improvement in the YMRS score at endpoint, was achieved by 81.81% of olanzapine-treated patients and 17.60% of asenapine-treated patients and the difference in response rate was statistically significant (P < 0.001). The rates of symptomatic remission (i.e. endpoint YMRS total score ≤12) were 50.0% in the olanzapine-treated patients and 11.76% for the asenapine treated patients and the difference were also statistically significant (P < 0.001).
Adverse events
Weight gain
Patients in the olanzapine group had a larger mean weight gain at week 3 from baseline when compared to the patients in the asenapine group (mean weight gain at week 3 was 1.9 kg and 0.87 kg, respectively). The mean of percentage weight change was statistically significant as compared to asenapine group (P = 0.02).
Extra pyramidal symptoms and other adverse events
Five (22.7%) of the patients in the olanzapine group had EPS as compared to 4 (23.5%) in the asenapine group, mostly in the form of tremors, rigidity, increased salivation and gait disturbances. Sedation-agitation scale (SAS) score was found to be significantly more in the asenapine group at week 1 when compared to olanzapine group [Table 3]. However, at week 2 and week 3, SAS scores were comparable between the two groups. This was due to use of trihexyphenidyl to alleviate EPS experienced by patients. Apart from EPS, other common adverse events reported by patients in olanzapine group were sedation, postural fall, somnolence, and increased appetite, whereas in asenapine group, dizziness, numbness in mouth, and headache were reported [Table 4].{Table 3}{Table 4}
Laboratory measures
There were no significant differences in rates of treatment-emergent abnormalities in hemogram, renal function tests, liver function tests, lipid profile and ECG between the two groups. However, FBS showed comparable increase of mean values in both the groups [Table 5]a, but, the increase in mean FBS values from baseline was significant in olanzapine group only [Table 5]b.{Table 5}
Discussion
The current study was carried out to compare the efficacy and tolerability of olanzapine and asenapine in the treatment of acute manic episode of bipolar disorder. This is the first Indian study conducted to compare the clinical efficacy and tolerability of asenapine and olanzapine.
The results from the current study show that olanzapine was more efficacious as compared with asenapine as there was statistically significant change in YMRS, CGI-BP, and PANSS scores at the end point of the study. In two earlier studies also the mean change in YMRS and CGI-BP score at week 3 with asenapine was comparatively less than that of olanzapine, although both the drugs were better than placebo in controlling manic symptoms. [13],[14] However, in another study, the reduction in PANSS scores with asenapine and olanzapine-treated manic patients after 3 weeks was comparable. [15]
While treating the acute manic episode, the treating psychiatrist is under lot of pressure to control the manic symptoms as early as possible in order to avoid further disturbance due to manic symptoms. Thus, the onset of action is very crucial. Previous studies comparing the two molecules have reported that the onset of action starts as early as day 2 for both asenapine and olanzapine when compared with placebo and this conclusion was based on reduction in mean YMRS score. [13],[14] In the current study, onset of action with olanzapine started after 4 days of initiation of treatment where as it came after 7 days with asenapine and thus the reduction in YMRS score was faster with olanzapine as compared with asenapine. In routine clinical practice, for treatment of acute manic episode in bipolar patients, antipsychotics are added with mood stabilizers for early reduction of acute manic symptoms and here the time for the onset of action is crucial. In such a situation, olanzapine should get preference over asenapine.
In addition to a reduction in total score, we also studied response and remission rate with olanzapine and asenapine at the end of 3 weeks. The results showed that both response rate and remission rate were better with olanzapine when compared to asenapine. In olanzapine group, more than 80% of patients showed a response when compared to approximately 18% in the asenapine group. An earlier study also reported similar findings. [9] However, in another study, both asenapine and olanzapine-treated subjects exhibited significantly greater response (42.3%; 50.0%) and remission (40.2%; 39.4%) compared with placebo (25.2% and 22.3%, respectively; P < 0.01). [14] In previous extension studies, asenapine showed comparable efficacy to olanzapine at end points and the differences observed at 3 weeks end points were narrowed between the groups suggesting that asenapine treated patients continue to improve even after improvement in acute manic symptoms. [15],[16] However, neither the treating team nor the family members can wait for such a long time to wait for response to come in case of acute manic symptoms.
The authors also tried to compare the safety of two drugs by studying effect on blood sugar, body weight, EPS and affect no other body organs. The results showed increase in mean body weight with both the drugs, however, the weight gain among patients in olanzapine group was statistically significant. Two earlier studies also found similar results. [13],[14] In fact olanzapine also showed significantly greater weight gain as compared to other drugs like lithium, divalproex and other second generation antipsychotics. [22],[23],[24] It has been reported that weight gain with olanzapine starts within first 3 weeks and it is postulated that early weight gain predicts substantial weight gain over long term. [25] The subjects in our study had significantly higher incidence of EPS related adverse events with both the drugs as compared to previous studies. [13],[14] The higher incidence of EPS could be attributed to higher average dose of olanzapine and asenapine used in the current study as compared to previous studies. [13],[14] However, similar to earlier studies, both the drugs did not have any adverse effect on the other body organs. [13],[14] The authors also tried to study the effect of olanzapine and asenapine on blood sugar and similar to earlier studies, there was increase in blood sugar levels as compared to baseline, but the increase in blood sugar levels were significantly more with olanzapine. [13],[14],[15],[16]
In contrast to earlier studies, asenapine did not show superior efficacy in controlling acute manic symptoms. However, it will be premature to draw such a conclusion on the basis of the current study as the present study had small sample size, and the duration of treatment was also short. To conclude, from the present study, as compared to asenapine, the response rate, and remission rate appeared to be better with olanzapine in addition to a faster onset of action. While looking at the safety profile, however, olanzapine led to greater increase in mean body weight and FBS as compared to asenapine.
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