Clinical outcomes of patients with bipolar disorder in the manic phase on valproate and olanzapine versus valproate and risperidone

doi:10.21203/rs.3.rs-3757932/v1

Purpose

Previous studies have shown that combining mood stabilizers and atypical antipsychotics is more effective than either treatment alone in bipolar disorder. The comparison of the two combinations is limited. We aim to compare the efficacy and adverse drug reactions of valproate plus olanzapine or risperidone combination treatment in the bipolar disorder, manic phase.

Method

In this 4-week study, 60 patients with DSM-V bipolar disorder in the psychotic manic phase were included and divided into either valproate plus olanzapine (n = 30) or risperidone (n = 30). The primary outcome was measured by the difference in mean total scores on the Young Mania Rating Scale (YMRS) and the Positive and Negative Syndrome Scale (PANSS). The secondary outcome for adverse effects was measured using the Naranjo ADR Probability Scale. The mean values obtained at weeks 0, 2, and 4 were compared.

Results

In our study, the mean difference in YMRS scores from baseline to week 4 in the olanzapine and risperidone groups was 13.9331.202 and 10.7671.164, respectively. These scores manifest significant changes within and between groups (p = < 0.001). A greater reduction was observed in the olanzapine group. There was no trend in the reduction of PANSS mean values between the groups, but a significant difference within the groups. However, a reduction was noted in the risperidone group. Adverse effects were observed more frequently during co-therapy with risperidone. Although, weight gain was notable in the olanzapine group.

Conclusion

All the results of our study showed that olanzapine in combination with valproate has slightly higher efficacy than risperidone.

bipolar disorder

mood stabilizer

atypical antipsychotics

co-therapy

Bipolar disorder is a mental disorder characterized by two phases, depression, and mania, which last from days to weeks. Despite many studies conducted, the real cause of bipolar disorder is still unclear. Studies show dopamine and serotonin play a role in their pathophysiology. It has been believed that genetics and environmental variables contribute to the incidence of bipolar disorder. Patients are likely to face higher rates of recurrence, psychosocial handicaps, and increased use of health services if the illness is not appropriately treated (Simon, 2003). Untreated bipolar disorder has negative effects on the patient (Goetzel, & Wang, S. 2003). One of the most frequent reasons for the recurrence of mood episodes is high non-adherence rates (Colom & Scott, J. 2005). Lack of understanding, negative attitudes toward medication, and co-occurring personality disorders are among the causes of non-adherence (Colom & Gasto, C. 2000).

Mood stabilizers and first-generation and second-generation antipsychotics have long been the primary mode of treatment of bipolar mania with and without psychotic features. An investigation has revealed that some guidelines for the management of bipolar disorder suggest monotherapy with mood stabilizers or second-generation antipsychotic drugs as frontline therapy, whereas others recommend a combination of both agents. Mood stabilizers widely used in bipolar disorder are lithium carbonate, and valproic acid/valproate. Olanzapine and risperidone are widely suggested atypical antipsychotic medications for individuals with bipolar disorder who experience acute manic episodes. A great deal of studies has been reported combination therapy of mood stabilizers and antipsychotics is more efficacious than monotherapy of either mood stabilizers or antipsychotics in bipolar disorder. The studies to compare two combination treatments are limited. This investigation seeks to assess and compare the effectiveness of the combination of valproate with olanzapine or risperidone in bipolar disorder in mania episodes.

We conducted a prospective observational study on 60 patients with DSM-V Bipolar disorder in manic episodes treated with a combination of valproate with olanzapine or risperidone over 8 months in a tertiary care hospital. All procedures were approved by the institutional research ethics committee, and performed in accordance with the recommendations of the Declaration of Helsinki on biomedical research involving human subjects. The total subjects were divided into two groups. Group A (n = 30) patients were treated with valproate-olanzapine, whereas Group B (n = 30) was with valproate-risperidone combinations. Written informed consent was obtained from all subjects. This study hypothesized that the clinical outcomes of valproate plus olanzapine therapy are non-inferior to valproate plus risperidone therapy in patients with bipolar mania.

Inclusion criteria:

Patients who meet DSM V criteria for bipolar disorder.
Patients with age ≥ 18 years
Patients with bipolar disorder who take valproate-olanzapine and valproate-risperidone treatments.

Exclusion criteria:

Pregnant and lactating women.
Patients who have experienced seizures (including seizure disorder), stroke, severe head injury, or any other condition that increases their risk of seizures.
Patients without psychotic symptoms.

Demographic details, medication history, symptoms, and comorbidities were collected during admission or outpatient consult. All subjects were evaluated at weeks 0, 2, and 4. The effectiveness of two different treatment groups was measured with rating scales such as YMRS and PANSS during their follow-up. YMRS is used to assess the presence and severity of mania symptoms, and PANSS determines the severity of psychotic features in mania patients. The causality of ADRs in both groups was assessed by Naranjo ADR Probability Scale. But the study did not include the doses of either of any drugs. In the end, the chi-square test and student’s t-test were used to analyse the data; a P-value of 0.05 or lower was considered statistically significant. The conclusion was based on the limited sample size and study duration.

3.1 AGE AND GENDER

Table 1

mean and standard deviation of age and gender distribution in group A and group B
Characteristics	Valproate-olanzapine	Valproate-risperidone
Age (Mean ± SD)	43.23 ± 16.91	44.50 ± 15.2
Female & male	60% & 40%	53.3% & 46.7%

Note: The was no significant difference between the two groups in baseline characteristics (Table 1). The age distribution of both groups shows a maximum number of patients belonging to the age group 20–29 years, and female was the most prominent gender in both groups than male gender.

3.2 BIPOLAR MANIA SYMPTOMS

Note In the current study, the major symptoms observed in patients in both group A and group B (Fig. 1) were irritability (86.7% & 80%), sleep disturbance (76.7% & 80%), and anxiety (80% & 76.7%). Irritability was observed as more significant than other symptoms.

3.3 MEDICAL COMORBIDITIES ASSOCIATED WITH BIPOLAR DISORDER

Note In this study, patients in group A and group B had systemic hypertension (20% & 17%), type 2 diabetes mellitus (10% & 20%), and hypothyroidism (13% & 23%) as the highest common medical comorbidities associated with bipolar mania (Fig. 2).

3.4 MEAN YMRS SCORES

Table 2

mean YMRS scores of patients in group A and group B
No. Of weeks	MEAN ± SD		p-value
No. Of weeks	Valproate-olanzapine	Valproate-risperidone	p-value
Week 0	17.13 ± 7.015	16.67 ± 7.406	.803
Week 2	9.13 ± 6.061	10.43 ± 5.811	.400

Note There was a trend in value reduction between week 0 and week 4 in both groups (p-value < 0.001), and reduction was shown higher in group A (Fig. 3). P < 0.05 indicated significance between the groups at the end of the study.

3.5 MEAN PANSS SCORE

Table 3

mean PANSS score of patients in group A and group B
No. Of weeks	Vaproate-olanzapine		Valproate-risperidone		the p-value in between group
No. Of weeks	mean ± SD	p-value within group	mean ± SD	p-value within group	the p-value in between group
Week 0	59.63 ± 14.109	-	55.50 ± 14.476	-	.267
Week 2	47.60 ± 10.153	< 0.001	44.80 ± 11.544	< 0.001	.323
Week 4	38.87 ± 5.380	< 0.001	37.97 ± 9.550	< 0.001	.655

Note In Fig. 4, statistically there was no trend in the value of reduction between the groups, but there was significance within the group (p value < 0.001).

3.6 BODY MASS INDEX (BMI)

Table 4

mean BMI of patients in group A and group B
No. Of weeks	Valproate-olanzapine		Valproate-risperidone		P-value between group
No. Of weeks	mean ± SD	p-value within group	mean ± SD	p-value within group	P-value between group
Week 0	25.34 ± 4.36	-	25.04 ± 4.058	-	0.785
Week 2	26.75 ± 4.48	< 0.001	25.88 ± 4.089	< 0.001	0.422
Week 4	28.136 ± 4.584	< 0.001	26.59 ± 4338	< 0.001	0.185

Note The p-value < 0.001 of BMI of study patients from week 0 to week 4 in group A and group B was found to be significant within the group. Group A showed more rise than group B (Fig. 5).

3.7 COMMON ADVERSE EFFECTS

Table 5

common adverse effects observed in patients of group A and group B
Adverse Effects	Valproate-olanzapine (%)	Valproate-risperidone (%)
Weight gain	40	16.7
Daytime sleep	6.7	13.3
fatigue	10	13.3
constipation	6.7	10

Note: Weight gain, daytime sleep, fatigue, and constipation were the most common ADRs found in both groups A and B

All subjects in this observational study have completed the course. The combination treatment of olanzapine and risperidone with valproate is well tolerated for up to 4 weeks. In addition to being D2 receptor antagonists, second-generation antipsychotics like olanzapine, quetiapine, and risperidone have an affinity for serotonin 5-hydroxytryptamine receptors and adrenergic receptors. Several studies show olanzapine combination therapy with valproate is more efficacious than olanzapine or valproate monotherapy (Xu, L., & Lin, Z. 2015). Likewise, risperidone combination therapy is more effective than risperidone monotherapy in reducing the severity of manic symptoms.

According to Ghaemi et al.'s 1999 study risperidone has bidirectional mood-stabilizing properties (Ghaemi,1997), (Ghaemi, & S. N.,1999). In six investigations involving individuals with schizoaffective or bipolar disorder, both with and without psychosis, the mean response rate was reported to be 51% (Ghaemi, & S. N.,1997), (Jacobsen, F. M. (1995), (Tohen, M.,1996), (Ghaemi, S. N., & Sachs, G. S. (1997), (Dwight 1994), (Sajatovic, M.,1996). There were no reports of mania being induced in any of the four studies where risperidone was used in conjunction with mood stabilizers. Risperidone (1–6 mg/day) and placebo were compared as add-on-therapy to lithium or divalproex in a randomized, 3-week, double-blind, multicentre trial by Sachs et al. for the acute treatment of bipolar mania (Sachs, G. 1999). Patients who received risperidone in addition to a mood stabiliser experienced a statistically significant improvement in their YMRS scores (p = .009) compared to those who received a placebo and a mood stabiliser. Tohen et al. studied patients with bipolar disorder who had completed acute therapy with olanzapine integrated with lithium or valproate and discovered that during an 18-month trial,

In contrast to 36.7% of patients taking olanzapine, 55.3% of patients receiving a placebo relapsed into either mania or bipolar depression (p = .149). Patients receiving a placebo had a considerably shorter time until a bipolar recurrence than those receiving olanzapine (Tohen, M. F., & Bowden, C. L. (2002). Findings from other studies suggest that in bipolar mania patients with inadequate responsiveness to monotherapy with mood stabilizers, their combination with olanzapine provides more efficacy (Tohen, M &. Chengappa, K. R., 2002).

In this present study, the rapid onset of action in both groups is shown by the mean YMRS score at baseline and week 2. The YMRS score significantly decreased from week 2 to baseline, and this pattern was observed throughout the entire study in group A and group B (P < 0.001), and group A appears to have more reduction than group B (Fig. 3). The fact that group A showed more reduction than group B, indicated that valproate-olanzapine treatment was better for reducing mania.

Studies show that olanzapine can produce efficacy in managing bipolar manic episodes as quickly as 1 week after the start of treatment (Vieta, E., 2008). In another study, YMRS scores in the risperidone group improved rapidly with greater reductions at week 1 (Yatham, L. N., 2003). The present study also found that olanzapine and risperidone combination therapies showed similar efficacy by YMRS score within 2 weeks of treatment but were more effective in olanzapine treatment. Except Sachs et al. study's visit-wise analysis and many other studies concluded that olanzapine and risperidone are equally efficacious and safe in the treatment of the manic phase of bipolar disorder.

Results from studies conducted by Elionor Nehme et al. demonstrate that a significant number of patients with bipolar disorder experience at least one psychotic symptom during a manic episode (Nehme, E.,2018). Comparable to our study, Canuso et al. found that bipolar disorder with psychosis resulted in higher scores on the six PANSS scale items of grandiosity, delusions, lack of judgment/insight, excitement, persecution, and hostility (Canuso.,2008).

On the PANSS positive scale, the mean scores exhibit a trend of value reduction from the baseline to the end of the study, and this trend is significant within the groups (P < 0.001). The PANSS negative scores show a decrease in value from week 0 to week 2 whereas a pattern of rise from week 2 to week 4 due to the psychotic symptoms masked was exhibited after week 2. There was significance within groups (P < 0.001) and a continuous decline in the PANSS total scores from baseline to week 4. The reduction was greater in group B indicating better effectiveness in reducing psychotic features in valproate-risperidone treatment than in the valproate-olanzapine group.

Common treatment-emergent adverse events during this study were increased weight, daytime sleep, fatigue, and constipation. The olanzapine group experienced a significantly larger mean weight change. Antipsychotics primarily increase appetite, which is how it makes people gain weight. The complex process of controlling appetite and food intake is carried out by the region of the brain called the hypothalamus. Several researches had been established that neurotransmitter receptors in the brain appear to be influenced by the serotonin 5-HT2C and 5-HT1A receptors, histamine H1 receptor, and dopamine D2 receptor, among others (Fleischhacker, 2010). The ability of different antipsychotics to inhibit these receptors varies, which helps to explain how differently they may cause weight gain (Henderson, 2015), (Mitchell, J. E. (2011). The histamine H1 and serotonin 5-HT2C receptors are highly bound by the weight-gain-risky medications olanzapine and clozapine.

Our study found that both the valproate-olanzapine group and valproate-risperidone group combination therapies are effective in patients with bipolar mania. YMRS scores showed the olanzapine-valproate group was more effective than the risperidone-valproate group in managing mania. Whereas the PANSS score manifested that risperidone-valproate is more effective in reducing psychotic symptoms. In terms of the incidence of ADRs, olanzapine has fewer ADRs than risperidone.

The limitations of our study include the exclusion of the strength of the drugs and less sample population with only psychotic symptoms. The generalizability of this study is limited to 4 weeks. Future areas of research can be studied in multicenter with many populations incorporating drug dosage and patients with non-psychotic features.

Considering all factors used in the study, we found that the valproate-olanzapine combination treatment is more effective than the valproate-risperidone combination treatment.

Funding:

Not applicable

Conflicts of interest:

The authors declare that they have no conflict of interest.

Ethics approval:

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Ethics Committee of Amrita Institute of Medical Sciences held on 22/10/2022 (IEC-AIMS-2022-PHARM-297).

Consent to participate:

Informed consent was obtained from all individual participants included in the study.

Consent for publication:

Not applicable

Author’s contribution:

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Anusree P, Remya Reghu and Dr Bindu Menon. The first draft of the manuscript was written by Anusree P and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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No competing interests reported.

Clinical outcomes of patients with bipolar disorder in the manic phase on valproate and olanzapine versus valproate and risperidone

Status:

Version 1

Abstract

Purpose

Method

Results

Conclusion

Figures

1. INTRODUCTION

2. METHODS

3. RESULTS

3.1 AGE AND GENDER

3.2 BIPOLAR MANIA SYMPTOMS

3.3 MEDICAL COMORBIDITIES ASSOCIATED WITH BIPOLAR DISORDER

3.4 MEAN YMRS SCORES

3.5 MEAN PANSS SCORE

3.6 BODY MASS INDEX (BMI)

3.7 COMMON ADVERSE EFFECTS

4. DISCUSSION

5. CONCLUSION

Declarations

References

Additional Declarations

Status:

Version 1