- Email: [email protected]
Safety and effectiveness of divalproex sodium extended release containing regimen in Indian patients with bipolar I disorder in continuation phase: Results of EASED registry
Asian Journal of Psychiatry 20 (2016) 32–38
Contents lists available at ScienceDirect
Asian Journal of Psychiatry journal homepage: www.elsevier.com/locate/ajp
Safety and effectiveness of divalproex sodium extended release containing regimen in Indian patients with bipolar I disorder in continuation phase: Results of EASED registry Nilesh Shah a,*, M.S. Reddy b, Sandeep Vohra c, Uday Chaudhuri d, Senthilnathan Mohanasundaram e a
L. T. M. Medical College and General Hospital, Mumbai, India Asha Bipolar Clinic, Asha Hospital, Hyderabad, India c Indraprastha Apollo Hospitals, New Delhi, India d Gaurinath Shastri Memorial Clinic, Kolkata, India e Sanofi, Mumbai, India b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 13 April 2015 Received in revised form 25 November 2015 Accepted 29 November 2015
The study was conducted to evaluate the safety and effectiveness of divalproex sodium XR containing regimen in patients with bipolar disorder (BPD) who are in continuation phase. It was an open-label, prospective, observational study conducted from July 2010 to December 2011 at 48 sites across India. Adult patients with bipolar I disorder of manic or mixed type fulfilling the DSM-IV criteria and who were in the continuation phase were included. Safety (primary outcome) was assessed by incidence of treatment emergent adverse events (AEs). Effectiveness (secondary outcome), was evaluated by proportion of patients who did not have a relapse, change in Clinical Global Impression Score-BP versionSeverity of Illness (CGI-BP) and Young’s Mania Rating Scale (YMRS) score. Data was recorded at three visits: visit-1 (baseline), visit-2 (end of 2 months 7 days) and visit-3 (end of 4 months 14 days), and summarised using descriptive statistics. p < 0.05 was considered statistically significant. A total of 489 and 468 patients were included in the safety and effectiveness analyses, respectively. Of the 66 AEs reported, 57 (89.0%) were mild and 7 (10.9%) were moderate (data missing for 2 events). In total, 75.0% (48/64) of the AEs were related to the study drug. No serious AEs reported (N = 64). No relapse observed in 93.3% of patients. There was a significant (p < 0.0001) reduction in the YMRS and CGI-BP scores from baseline to visit-3. Our study confirms the results of earlier studies in terms of good tolerability and effectiveness of divalproex sodium XR containing regimen in this study population. ß 2015 Elsevier B.V. All rights reserved.
Keywords: Bipolar disorder Valproic acid Depression Mania Safety
1. Introduction Bipolar disorder (BPD) causes unusual shifts in mood and is characterised by transition between depression and mania that affects one’s ability to function (Hirschfeld et al., 2000). The National Comorbidity Study reported a lifetime prevalence of nearly 4.0% for BPD patients worldwide (Andreasen and Black, 2006). Prevalence of 12-month and lifetime Diagnostic and Statistical Manual of Mental Disorder (DSM)—IV bipolar I disorder in U.S. population was 2.0% (95% confidence interval [CI] = 1.82 to 2.18) and 3.3% (95% CI = 2.76 to 3.84), respectively (Grant et al.,
* Corresponding author. Tel.: +91 022 24011984. E-mail address: [email protected] (N. Shah). http://dx.doi.org/10.1016/j.ajp.2015.11.009 1876-2018/ß 2015 Elsevier B.V. All rights reserved.
2005). The WHO World Mental Health survey data shows a 0.1% lifetime as well as 12-month prevalence of Bipolar Spectrum in India (Merikangas et al., 2011). However, BPDs, including both bipolar disorder I and II, are frequently not recognised, and thus remain undiagnosed and untreated (Hirschfeld et al., 2000). BPD imposes a significant economic burden on patients, their families and society as a whole (Dilsaver, 2011). Although there is lack of data on economic burden of BPD in India in published literature, it is likely to be significant. Additionally, patients and their families face significant social and interpersonal burden due to BPD. In a survey conducted in India, more than 90% of family members of patients with BPD reported care-related burden in the absence of clinical interventions (Maji et al., 2012). Similarly, half of the BPD patients showed negative outcomes with difficulties in inter-personal relationships (Chopra et al., 2010).
N. Shah et al. / Asian Journal of Psychiatry 20 (2016) 32–38
Several therapeutic modalities have been recommended for the treatment of BPD. Mood stabilisers, namely, lithium and divalproex are useful in preventing relapse in BPD (Bowden, 2000). Divalproex sodium, an anticonvulsant and mood stabiliser, is widely prescribed to treat BPD as well. Current guidelines recommend valproate (either divalproex or other formulations) as monotherapy or combination therapy with other agents as firstline or second-line treatment for bipolar depression (Goodwin, 2009; Grunze et al., 2010; Yatham et al., 2009). In fact, along with lithium, divalproex sodium or valproic acid is the most commonly prescribed medication for patients with Bipolar Disorder (2012). Lithium and valproate have also been used for the maintenance therapy in BPD (Hirschfeld et al., 2002). A randomised placebocontrolled multicentre study of divalproex sodium extended release (XR) in patients hospitalised for acute mania showed that it was safe and well-tolerated for the treatment of manic episodes (Bowden et al., 2006). A study which compared the efficacy of divalproex, lithium, and placebo in patients with bipolar I disorder demonstrated that divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse, particularly in patients with manic episodes (Gyulai et al., 2003). Similarly, higher response rates (Bowden et al., 2010) and greater remission rates (Bowden et al., 2008) have been seen with sodium valproate when compared to lithium in BPD patients suffering from manic episodes. A 12-week randomised, doubleblind, parallel group study on BPD patients showed that divalproex sodium was associated with a better adverse event (AE) profile and significantly less weight gain when compared to olanzapine (Zajecka et al., 2002). In a recent review by Cochrane group that included 6 randomised controlled trials comparing valproate with placebo, lithium, olazapine and lithium plus valproate combination, no difference in efficacy was found between valproate and lithium (Relative risk [RR] 1.02, 95% CI 0.87 to 1.20) though valproate group had fewer participants dropping out of treatment for any cause when compared with placebo or lithium (RR 0.82, 95% CI 0.71 to 0.95 and RR 0.87, 95% CI 0.77 to 0.98, respectively) (Cipriani et al., 2013). While there are international guidelines about appropriate therapeutic management of BPD, they are predominantly based on evidence gathered from large studies based in Western countries. The rational management of BPD in Indian patients is possible only in light of evidence gathered from contemporary clinical practice in India. There is a scarcity of data supporting the effectiveness and safety of divalproex sodium XR during the continuation phase of BPD patients in India. The current study was proposed to evaluate the safety and effectiveness of divalproex sodium XR (Depakote XR1) in patients with BPD and is the first of its kind in India. Primary objective of the study was to evaluate the safety of divalproex sodium XR containing regimen in patients with BPD in continuation phase. Secondary objective of the study was to evaluate the effectiveness of divalproex sodium XR containing regimen in patients with BPD in the continuation phase.
2. Materials and methods The present study was an open-label, single-arm, multicentre, prospective observational study, conducted from July 2010 to December 2011 at 48 sites across India by 48 investigators. The study was conducted according to the guidelines for Good Epidemiology Practice, the principles of Declaration of Helsinki of 1975, as revised in 2000, and in accordance with the local regulations of institutional review board/institutional ethics committee. Written, signed informed consent was obtained from each patient enrolled in the study.
33
Adult patients with bipolar I disorder of manic or mixed type (as per DSM-IV-TR criteria), who were treated for an acute episode and were in the continuation phase (defined as commencing once euthymia and resolution of psychosis have been achieved), (Sharma et al., 1997) and who were, prescribed divalproex sodium XR containing regimen by the investigator, were included in the study. Patients having any other clinically significant psychiatric disorder, cardiovascular, hepatic, neurological, endocrine or other major systemic disease were excluded from the study. Case report forms were used to collect data from source documents (patient file, prescription letters or any other relevant document) at three visits: visit 1 (baseline), visit 2 (end of 2 months 7 days) and visit 3 (end of 4 months 14 days). Demographic features, dose and duration for which divalproex sodium XR was taken, duration of BPD, concomitant medication use, relapse of mania associated with BPD and Clinical Global Impression Score-BP version-Severity of Illness (CGI-BP) and Young’s Mania Rating Scale (YMRS) score were recorded in the case report forms. The total number of AEs reported by patients and the severity, seriousness, and relationship of the AE to the study medication were analysed. Proportion of patients who discontinued study drug at visit 2 and visit 3 and the reasons for discontinuation were documented. Effectiveness of the drug was assessed by measuring the change in CGI-BP and YMRS at visit 2 (end of 2 months 7 days) and visit 3 (end of 4 months 14 days) compared to baseline (visit 1). Proportion of patients experiencing relapse were also recorded. 2.1. Statistical analysis Assuming that 23% of the patients would have shown treatment-emergent AEs, with confidence interval of 90% and precision of 3%, it was estimated that 529 patients would be required for the study. A sample size of 635 was determined for the study assuming a drop out of 20%. All categorical variables were presented as proportions and percentages. Continuous variables were reported as mean with standard deviation. A p-value <0.05 was considered statistically significant. All statistical analyses were carried out using SAS 9.1.3 (SAS Institute Inc., Cary, NC, USA). 3. Results 3.1. Patient disposition and demographics Out of the total 578 patients screened, 489 were included in the safety analyses and 468 were included in the effectiveness analyses; 474 patients completed the study. Patient disposition and the reasons for discontinuation have been summarised in Fig. 1. In the safety analyses set, 345 patients (70.6%) were male and 144 (29.4%, N = 489) were female, with a mean age of 35.6 11.1years. In the effectiveness analysis set, 331 (70.7%, N = 468) patients were male and 137 (29.3%, N = 468) patients were female, with a mean age 35.6 11.0 years. The mean duration of BPD was 69.2 82.2 months and the mean duration of acute episodes was 31 23.7 days. The mean dose of divalproex sodium XR taken was 907.9 316.1 mg/day and 883.5 300.8 mg/day during visit 2 and 3, respectively. Divalproex sodium XR was taken for a mean duration of 65.1 16.0 and 104.5 28.1 days for visit 2 and visit 3, respectively. Olanzapine was the most commonly used concomitant medication at visit 2 [n = 149 (44.6%)] and visit 3 [n = 119 (39.8%)] (Table 1). 3.2. Safety outcomes A total of 66 AEs were observed in 56 patients (11.5%, N = 489) during the study. Most frequently observed AEs were alopecia (2.5%, 12 events in 12 patients) and tremor (1.4%, 8 events in 7
34
N. Shah et al. / Asian Journal of Psychiatry 20 (2016) 32–38
Fig. 1. Patient disposition.
patients). Out of the 66 AEs reported, 57 (89.0%) were mild and 7 (10.9%) were moderate; this data was missing for 2 events. None of the AEs were serious (N = 64 since this data was missing for 2 events). A total of 48 (75.0%; N = 64) AEs were related to the study drug, whereas 16 (25.0%; N = 64) AEs were not related to the study drug; this data was missing for 2 events. Corrective treatment was given to 36 (57.1%; N = 63 since this data was missing for 3 events) patients. Discontinuation of divalproex sodium XR was reported in 4 AEs (6.3%, N = 63 since this data was missing for 3 events); in 2 events (of alopecia), divalproex sodium XR was discontinued permanently and in the other 2 events (1 of alopecia and 1 of headache), it was discontinued temporarily. Most of the AEs (28/62; 45.2%) were resolved, 12 (19.4%, N = 62) were being resolved, and 22 (35.5%, N = 62) did not resolve; this data was missing for 3 events and for 1 event the outcome was unknown. AEs reported during the current study have been summarised in (Table 2). 3.3. Effectiveness outcomes A total of 468 patients were included in the effectiveness analysis. Relapse was observed in 6.7% (n = 31) of the patients. Of the total 31 patients who suffered relapse, 9 suffered from episodes of depression, 14 from episodes of mania and 6 suffered both (data was missing for 2 patients). The summary of relapse associated with BPD and episodes of depression and mania have been listed in (Table 3). There was a significant reduction in the YMRS score (p < 0.0001) (Table 4) and CGI-BP depression, mania as well as overall scores (p < 0.0001) (Table 5). 4. Discussion This study was an open-label, prospective, observational study to estimate the safety and effectiveness of divalproex sodium XR containing regimen in patients with bipolar I disorder who were in the continuation phase. Divalproex sodium XR was well-tolerated with mild (89.0%) and moderate (10.9%) AEs. No serious AEs were reported in the study. No relapse was observed in 93.3% of the patients during the study. The change in the YMRS score and CGIBP score from baseline to visit 3 (end of 4 months 14 days) was statistically significant indicating that divalproex sodium XR containing regimen reduced the severity of illness and was effective in patients with bipolar I disorder. Incidence of weight gain, glucose dysregulation and metabolic changes are associated with BPD patients treated with antipsychotics
and antidepressants drugs (Hasnain et al., 2012). Weight gain and increased body mass index are the most common AEs related to divalproex sodium XR therapy (Bowden et al., 2006; Geller et al., 2012; Redden et al., 2009; Zajecka et al., 2002). In the current study, only 1.4% of patients with BPD experienced weight gain with divalproex sodium XR treatment. The overall incidence of AEs was low in the current study when compared with a previous randomised placebo-controlled study on divalproex sodium XR treatment (11.5%, N = 489 vs. 84%, N = 192), which reported somnolence (33%), nausea (28%) and dyspepsia (26%) as the most common AEs (Bowden et al., 2006). In another randomised study on divalproex sodium XR treatment, the reported AE rate for somnolence was 29% and rhinitis was 3% (Zajecka et al., 2002). In the current study, alopecia (2.5%, 12 events in 12 patients) and tremor (1.4%, 8 events in 7 patients) were the most common AEs, and somnolence occurred in only 1.4% (7 events in 7 patients), nausea in 0.4% (2 events in 2 patients), and rhinitis in 0.2% (1 event in 1 patient) of patients. Also, the documented AEs reflect the spectrum of complaints usually observed with divalproex sodium XR treatment. The minor side effects of divalproex sodium like sedation or gastrointestinal distress are common initially and typically resolve with continued treatment or dose adjustment (Hirschfeld et al., 2002). No AEs were reported by 88.5% of the study population, indicating that divalproex sodium XR was well-tolerated and safe in the study population. Due to the occurrence of AEs, out of 4 patients in whom the study drug was discontinued, 2 patients withdrew from the study, and in 6.3% (4/63) of the events, the study drug was discontinued. Similarly lower discontinuation rates, particularly related to AEs were reported in a previous study i.e. 26% and 6% for lithium and valproate, respectively (Bowden et al., 2008). The data from the present study is also consistent with the results of another 3 week study for acute mania in which divalproex sodium formulation was better tolerated and had limited discontinuations when compared to lithium (Bowden et al., 1994). Dose escalation in extended release of divalproex sodium is well tolerated in the patients with BPD (Stoner and Dahmen, 2007). An open-label study (Horne and Cunanan, 2003) which evaluated the safety and efficacy of divalproex sodium in switching patients from delayed release to extended release suggested that divalproex sodium XR was better tolerated and equally effective in treating patients with psychiatric illness. Moreover divalproex sodium XR in once daily dosage regimen improved patient compliance.
Table 1 Summary of concomitant medication. Visit 3
334
299
Drug
n (%)
Alprazolam Amisulpride Amitriptyline Aripiprazole Atenolol Becosules Benfotiamine Biotin Carbamazepine Chlordiazepoxide Chlorpromazine Clonazepam Clozapine Domperidone Dosulepin Escitalopram Fluoxetine Fluphenazine Fluvoxamine Glimepiride Haloperidol Lactulose Lamotrigine Levothyroxine Sodium Lithium Lithium Carbonate Lorazepam Metformin Nitrazepam Olanzapine Oxcarbazepine Paliperidone Paracetamol Pioglitazone Pramipexole Promethazine Propranolol Psycholeptics and psychoanaleptics in combination Quetiapine Ranitidine Risperidone Sertraline Topiramate Trifluoperazine Trihexyphenidyl Valproate Semisodium
1(0.3) 10(3.0) 2(0.6) 6(1.8) 1(0.3) 1(0.3) 1(0.3) 2(0.6) 5(1.5) 2(0.6) 7(2.1) 59(17.7) 9(2.7) 1(0.3) 3(0.9) 5(1.5) 2(0.6) 2(0.6) 2(0.6) 1(0.3) 32(9.6) 1(0.3) 7(2.1) 1(0.3) 68(20.4) 12(3.6) 48(14.4) 2(0.6) 6(1.8%) 149(44.6) 8(2.4) 1(0.3) 0 1(0.3) 1(0.3) 2(0.6) 3(0.9) 4(1.2)
1.0 175.0 (108.64) 7.5 (3.54) 10.0 (3.16) 100.0 – 100.0 10.0 360.0 (167.33) 2.5 (3.5285) 101.5 (148.85) 2.2 (4.51) 69.4 (41.04) 0.0 25.1 (43.26) 6.0 (5.47) 20.0 (0.00) 25.0 35.0 (21.21) 1.5 8.8 (6.50) – 146.4 (68.36) 50.0 724.3 (232.82) 908.3 (242.930) 1.9 (1.00) 875.0 (883.88) 10.0 (0.00) 9.7 (6.25) 637.5 (250.36) 9.0 – 15.0 0.130 17.5 (10.61) 30.0 (17.32) 10.0 (6.12)
51(15.3) 2(0.6) 64(19.2) 1(0.3) 4(1.2) 5(1.5) 50(15.0) 39(11.7)
234.3 (134.62) 300.0 (0.00) 5.516 (13.50) 100.0 37.5 (14.4338) 10.0 (5.00) 3.1 (1.69) 843.8 (251.20)
Dose (mg/day) Mean (SD)
Duration (days) Median (min-max) 1.0 (1.00–1.00) 200.0 (0.05–300.00) 7.5 (5.00–10.00) 10.0 (5.00–15.00) 100.0 (100.00–100.00) – 100.0 (100.00–100.00) 10.0 (10.00–10.00) 400.0 (200.00–600.00) 2.5 (0.01–5.00) 10.000 (0.01–400.00) 1.0(0.00–25.00) 50.0 (25.00–150.00) 0.0 (0.02–0.02) 0.1 (0.08–75.00) 10.0 (0.01–10.00) 20.0 (20.00–20.00) 25.0 (25.00–25.00) 35.0 (20.00–50.00) 1.5 (1.50–1.50) 7.5 (0.00–30.00) – 200.0 (50.00–200.00) 50.0 (50.00–50.00) 900.0 (0.80–1350.00) 900.0 (600.00–1500.00) 2.0 (0.00–6.00) 875.0 (250.00–1500.00) 10.0 (10.00–10.00) 10.0 (0.01–30.00) 600.0 (300.00–1200.00) 9.0 (9.00–9.00) – 15.0 (15.00–15.00) 0.1 (0.13–0.13) 17.5 (10.00–25.00) 40.0 (10.00–40.00) 10.0 (0.01–15.00)
200.0 300.0 3.0 100.0 37.5 10.0 3.0 1000.0
(0.10–600.00) (300.00–300.00) (0.00–100.00) (100.00–100.00) (25.00–50.00) (5.00–15.00) (0.00–8.00) (500.00–1500.00)
n (%)
Mean (SD)
Median (min-max)
61.0 267.9 (297.22) 69.5 (12.02) 279.8 (435.50) 152.0 30.0 92.0 32.5 (3.54) 71.0 (22.36) 202.0 (147.08) 240.6(250.61) 128.5 (201.96) 200.3 (240.83) 92.0 101.7 (63.74) 99.2 (101.95) 45.5 (21.92) 328.0 (197.99) 45.5 (21.92) 77.0 538.4 (1348.80) 3.0 235.7 (173.23) 51.0 729.0 (1258.61) 468.4 (294.33) 160.5 (258.90) 3165.5 (3874.24) 721.0 (766.60) 410.5 (1852.20) 158.3 (93.10) 287.0 – 77.0 61.0 61.0 (0.00) 152.0 (185.11) 60.8 (43.67)
61.0 122.0 69.5 78.0 152.0 30.0 92.0 32.5 61.0 202.0 152.0 61.0 109.0 92.0 123.0 45.0 45.5 328.0 45.5 77.0 146.0 3.0 244.0 51.0 183.0 477.5 63.0 3165.5 487.0 81.0 137.0 287.0 – 77.0 61.0 61.0 61.0 30.0
211.7 38.0 268.0 244.0 76.3 456.6 216.2 119.7
(231.81) (32.53) (508.07) (39.89) (800.59) (341.46) (170.48)
77.0 38.0 82.0 244.0 76.0 122.0 93.5 61.0
(61–61) (61–791) (61–78) (61–1157) (152–152) (30–30) (92–92) (30–35) (61–111) (98–306) (91–791) (15–1157) (61–731) (92–92) (30–152) (30–268) (30–61) (188–468) (30–61) (77–77) (10–7366) (3–3) (38–426) (51–51) (30–7366) (61–974) (5–1157) (426–5905) (91–2043) (4–22) (69–335) (287–287) (77–77) (61–61) (61–61) (30–365) (30–123)
(30–980) (15–61) (30–3044) (244–244) (30–123) (61–1887) (10–1522) (28–974)
Dose (mg/day)
Duration (days)
Mean (SD)
Median (min-max)
Mean (SD)
Median (min-max)
1(0.3) 11(3.7) 2(0.7) 5(1.7) 1(0.3) 0 1(0.3) 1(0.3) 5(1.7) 2(0.7) 4(1.3) 46(15.4) 7(2.3) 1(0.3) 3(1.0) 8(2.7) 0 2(0.7) 0 0 20(6.7) 1(0.3) 7(2.3) 1(0.3) 59(19.7) 11(3.7) 30 (10.0) 2(0.7) 6(2.0) 119(39.8) 8(2.7) 1(0.3) 3(1.0) 0 2(0.7) 1(0.3) 4(1.3) 2(0.7)
25.0 168.2 (105.52) 5.0 (0.00) 12.0 (2.74) 100.0 – 0.10 0.0 240.0 (114.02) 0.1 (0.06) 137.5 (188.74) 3.4 (9.80) 128.6 (85.91) 0.0 25.1 (43.26) 6.3 (5.7473) – 25.0 (0.00) – – 9.5 (7.05) – 164.29 (62.68) 50.0 727.9 (229.52) 825.5 (364.87) 2.2 (1.12) 875.00(883.88) 10.0 (0.00) 9.0 (6.73) 637.5 (250.36) 9.0 1166.6 (577.350 – 0.1 (0.00) 25.0 25.0 (12.91) 0.0 (0.00)
25.0 (25.00–25.00) 200.0 (0.05–300.00) 5.0 (5.00–5.00) 10.0 (10.00–15.00) 100.0 (100.00–100.00) – 0.1 (0.10–0.10) 0.0 (0.01–0.01) 200.0 (100.00–400.00) 0.06 (0.01–0.10) 75.005 (0.01–400.00) 1.000 (0.01–62.50) 100.0 (50.00–300.00) 0.0 (0.02–0.02) 0.1 (0.08–75.00) 7.5 (0.01–15.00) – 25.0 (25.00–25.00) – – 10.0 (0.00–30.00) – 200.0 (50.00–200.00) 50.0 (50.00,50.00) 800.0 (0.60–1350.00) 900.0 (80.00–1500.00) 2.0 (1.00–6.00) 875.0 (250.00–1500.00) 10.0 (10.00–10.00) 5.0 (0.01–30.00) 600.0 (300.00–1200.00) 9.0 (9.00–9.00) 1500.0 (500.00–1500.00) – 0.1 (0.13–0.13) 25.0 (25.00–25.00) 25.0 (10.00–40.00) 0.0 (0.01–0.01)
30.0 282.5 (309.62) 131.0 (12.73) 366.8 (484.73) 213.0 – 154.0 61.0 89.4 (63.50) 263.0 (148.49) 391.3 (316.70) 159.4 (223.48) 167.3 (253.22) 155.0 178.7 (38.89) 124.8(104.58) – 388.5 (197.28) – – 722.2 (1616.60) 3.0 295.9 (172.54) 114.0 773.2 (1262.96) 613.4 (520.88) 281.1 (346.10) 3226.5 (3874.24) 771.8 (761.01) 335.8 (571.26) 210.8 (104.45) 344.0 1166.667(577.350 – 61.0 (0.00) 99.0 152.0 (187.74) 199.5 (20.51)
30.0 (30–30) 154.0 (61–852) 131.0 (122–140) 152.0 (61–1218) 213.0 (213–213) – 154.0 (154–154) 61.0 (61–61) 61.0 (61–203) 263.0 (158–368) 277.5 (158–852) 61.0 (30–1218) 61.0 (20–731) 155.0 (155–155) 185.0 (137–214) 132.0 (10–327) – 388.5 (249–528) – – 258.5 (30–7427) 3.0(3–3) 295.0 (101–487) 114.0 (114–114) 254.0 (45–7427) 536.0 (99–1913) 122.0 (61–1218) 3226.5 (487–5966) 548.0 (152–2104) 147.0 (15–3774) 198.0 (63–396) 344.0 (344–344) 3.0 (2–3) – 61.0 (61–61) 99.0 (99–99) 76.0 (30–426) 199.5 (185–214)
45(15.1) 1(0.3) 50(16.7) 1(0.3) 2(0.7) 4(1.3) 35 (11.7) 36(12.0)
238.6 (167.69) 300.00 2.530(1.49) 100.0 37.5 (17.68) 8.8 (4.79) 3.0 (1.56) 784.7 (247.51)
200.0 300.0 2.0 100.0 37.5 7.5 2.0 1000.0
(0.10–600.00) (300.00–300.00) (0.00–6.00) (100.00–100.00) (25.00–50.00) (5.00–15.00) (0.00–8.00) (250.00–1000.00)
277.0 76.0 427.1 304.0 162.5 570.8 313.7 178.9
(268.73) (768.66) (187.38) (920.96) (405.76) (272.56)
155.0 76.0 152.0 304.0 162.5 137.0 183.0 61.0
N. Shah et al. / Asian Journal of Psychiatry 20 (2016) 32–38
Visit 2 (N = 488) No. patients on concomitant medication (N)
(2–1049) (76–76) (30–3805) (304–304) (30–295) (61–1948) (30–1583) (30–1157) 35
N. Shah et al. / Asian Journal of Psychiatry 20 (2016) 32–38
(213–213)
(313–313) (154–396) (30–149)
313.0 244.0 61.0 – 213.0 (200.00–200.00)
313.0 264.7 (122.32) 80.0 (61.73) – 213.0 (225.00–225.00) (0.02–80.00) (5.00–6.25)
225.0 20.0 5.0 – 200.0 225.0 33.3 (41.63) 5.4 (0.72) – 200.0 1(0.3) 3(1.0) 3(1.0) 0 1(0.3) (253–253) (92–335) (61–92) (30–30) 253.0 183.0 61.0 30.0 – 253.0 203.3(122.77) 71.3(17.90) 30.0 – 225.0 (225.00–225.00) 20.0 (0.02–80.00) 10.0 (5.00–12.50) – – 225.0 33.3 (41.63) 9.2 (3.82) – – 1(0.3) 3(0.9) 3(0.9) 1(0.3) 0
n (%) Drug
Venlafaxine Ziprasidone Zolpidem Zuclopenthixol Zuclopenthixol Decanoate
Duration (days) Dose (mg/day) n (%) Duration (days)
Mean (SD) Mean (SD)
334
Visit 2 (N = 488) Table 1 (Continued )
No. patients on concomitant medication (N)
Median (min-max) Dose (mg/day)
Median (min-max)
299
Visit 3
Mean (SD)
Median (min-max)
Mean (SD)
Median (min-max)
36
Table 2 Adverse events related with the study drug (N = 489). Adverse events
No. of events
Patients, n (%)
Alopecia Tremors Somnolence Weight gain Headache Constipation Gastritis Nausea Peripheral edema Pyrexia Appetite disorder Increased appetite Dizziness Vomiting Insomnia Amenorrhea Rhinitis Upper respiratory tract infection
12 8 7 7 6 5 4 2 2 2 2 2 2 1 1 1 1 1
12 7 7 7 5 5 4 2 2 2 2 2 2 1 1 1 1 1
(2.5) (1.4) (1.4) (1.4) (1.0) (1.0) (0.8) (0.4) (0.4) (0.4) (0.4) (0.4) (0.4) (0.2) (0.2) (0.2) (0.2) (0.2)
Table 3 Summary of relapse associated with bipolar disorder. Variables
Visit 2 (N = 467)
Visit 3 (N = 463)
Overall (N = 468)
Total patients analysed for relapse associated with BPD (N) Yes, n (%) No, n (%) Data missing, (n) Total number of relapse, (n) Mean (SD) Median Min, Max Missing, (n)
452
447
463
22 (4.9) 430 (95.1) 15 22 1.8 (1.97) 1.0 1, 10 0
22 (4.9) 425 (95.1) 16 20 1.9 (2.05) 1.0 1, 10 2
31(6.7) 432 (93.3) 5 29 2.7 (3.71) 1.0 1, 20 2
BPD = Bipolar disorder patients, SD = Standard deviation.
Divalproex sodium XR therapy provided reliable anti-manic effect in real-life practice with no relapse in 93.3% of patients in the current study. YMRS scores are often utilised in defining response in patients even if definitive remission is not seen (Patel et al., 2007). In the current study, there was a significant reduction in the mean YMRS score ( 4.5 6.2) from baseline to visit 3, which indicated that patients showed response to divalproex sodium XR administration. This is in line with an earlier study reporting significant reduction in the mean YMRS scores (mean change: 12.4 8.07) with divalproex sodium XR (Redden et al., 2009). In a randomised study, 51.7% of patients in the lithium group showed response to treatment (50% reduction in YMRS scores) in comparison to 56.7% of patients in valproate sodium group (Mosolov et al., 2009). In a comparative open-label 3-month study of lithium and sodium valproate, higher remission rates were reported in sodium valproate group than in lithium group (72.3% vs. 66.5%) (Bowden et al., 2008)). In another placebo-controlled trial, response rates of 48% were seen in divalproex sodium XR group when compared to 34% in placebo group (Bowden et al., 2006). The CGI scale is used to quantify and track patient progress and treatment response over time (Busner and Targum, 2007). The CGIBP provides an accurate and reliable global assessment of illness, severity and degree of improvement occurring in mania, depression and in the overall illness on a given treatment (Spearing et al., 1997). In an earlier study, CGI-BP was measured as primary outcome where divalproex demonstrated long-term antidepressant effects in patients with BPD (Ghaemi and Goodwin, 2001). There was significant reduction in CGI-BP scores in the current study which suggests consistent improvements in both mania and depression status of patients. On the contrary, data from a recent study on acute efficacy of divalproex sodium XR on mood stabiliser
N. Shah et al. / Asian Journal of Psychiatry 20 (2016) 32–38
37
Table 4 Change from baseline in Young’s Mania Rating Scale at Visit 2 and 3 for overall patients. Descriptive statistics
Visit 1 (N = 468)
Visit 2 (N = 467)
Total number (N) Mean (SD) Median Min, Max Missing
468 6.9 (7.4) 6 0, 51 0
465 4.0 (4.8) 3 0, 38 2
Change at visit 2 from baseline 465 3.0 (4.9) 2 13, 45 0
p-Value
Visit 3 (N = 463)
Change at visit 3 from baseline
p-Value
<0.0001a
456 2.5 (3.6) 2 0, 29 7
456 4.5 (6.15) 3 3, 48 0
<0.0001a
a Wilcoxon Signed Rank Test is used to test the mean difference in scores between the baseline and the two visits; test was done at 5% level of significance; p 0.05 indicates significance. SD = Standard deviation.
Table 5 Change from baseline in Clinical Global Impression Score—BP version-Severity of Illness at visit 2 and 3. Severity of Illness
Visit 1 (N = 468) Visit 2 (N = 467) Change at visit 2 from baseline p-Value
461 Mania, (n) Mean (SD) 2.1 (1.33) Depression, (n) 408 Mean (SD) 1.3 (0.89) Overall Bipolar illness, (n) 442 Mean (SD) 2.0 (1.27)
457 1.7 (1.02) 409 1.1 (0.54) 440 1.7 (1.13)
457 0.5 (1.03) 402 0.2 (0.93) 437 0.3 (1.01)
Visit 3 (N = 463) Change at visit 3 from baseline p-Value
442 1.5 (0.93) 401 <0.0001 1.1 (0.66) 442 <0.0001 1.5 (0.99) <0.0001
442 0.7 (1.10) 394 0.2 (1.03) 429 0.6 (1.06)
<0.0001 <0.0001 <0.0001
Wilcoxon Signed Rank Test is used to test the mean difference in scores between the baseline and the two visits; test was done at 5% level of significance; p 0.05 indicates significance; CGI-BP score was calculated as 1 = Normal/not ill, 2 = Minimally ill, 3 = Mildly ill, 4 = Moderately ill, 5 = Markedly ill, 6 = Severely ill, 7 = Very severely ill. SD = Standard deviation.
naı¨ve patients with BPD showed no significant change in the CGI scores (Muzina et al., 2011). Significant improvements from baseline in YMRS and CGI-BP score were also observed with divalproex sodium in the treatment of paediatric mixed mania over a 6-month period (Pavuluri et al., 2005). BPD remains a largely unexplored issue in the realm of psychiatric illnesses in India. Nonetheless, the burden that BPD imposes on patients can clearly be surmised from the current literature on the subject, however scant. The availability of effective therapeutic options is essential to addressing the issues faced by people with BPD. The current study is the first of its kind in addressing the question of safety and effectiveness of divalproex sodium XR, in Indian patients. 4.1. Study limitations The results must be interpreted with caution as the study did not meet the target sample size recruitment. Additionally, there were no multivariate/stratified analyses to rule out the effect of confounders like concomitant medications. Depression was not assessed by a symptom driven scale like HAM-D or equivalent and the follow-up period of 4 months may be considered short to evaluate the prophylactic efficacy of a mood stabiliser. The openlabel, single-arm, observational nature of the study could be a source for potential bias (like selection bias). Nonetheless, this study establishes the evidence for further investigation of divalproex sodium XR in randomised clinical trials as well as observational registries in India. In summary, subjects with bipolar I disorder in continuation phase treated with divalproex containing regimen, showed improvements in YMRS and CGI-BP score indicating a reduction in the severity of the illness. Majority of the patients responded to divalproex sodium XR during the treatment period. Relapse associated with BPD was not seen in majority of patients. Divalproex sodium XR was well-tolerated with mild and moderate AEs. No serious AEs reported. The study results correspond well with other studies where efficacy and good tolerability of divalproex sodium in the treatment and maintenance of acute and mixed mania is established in short-term/placebo-controlled/ parallel-group trials, with effectiveness comparable to other mood
stabilizing agents like lithium. Thus, it can be concluded that divalproex sodium XR containing regimen confirms the results of earlier studies in terms of good tolerability and effectiveness in Indian patients with bipolar I disorder in continuation phase. Conflict of interest statement Vohra S., Chaudhuri U. and Reddy M.S. have been invited speakers in meetings by Sanofi and received honoraria as a consultant. Shah N. has participated as invited faculty in the scientific meetings organised by Sanofi. All authors have received remuneration for the time spent in conducting the study from Sanofi. Mohanasundaram S., is an employee of Sanofi. Funding This study was sponsored by Sanofi (India). Medical writing support for preparing this manuscript was funded by Sanofi (India). Author’s contribution All authors have contributed substantially to the conception and design of the study and the acquisition of data; additionally, they have revised the article critically for important intellectual content and have provided their approval for publication. Acknowledgements The authors acknowledge Jeevan Scientific Technology Limited (Hyderabad, India), and Anahita Gouri and Dr. Alina Gomes of Sanofi (India) for providing writing and editing assistance in developing this manuscript. The authors also thank all the investigators who participated in the study. We would like to thank the following participating physicians who recruited patients—Dr. Debashis Ray, Kolkata; Dr. Partha Dutta, Kolkata; Dr. Amarnath Mallik, Kolkata; Dr. Abhay Kumar Dey, Howrah; Dr. Bijoy Chaudhuri, Guwahati; Dr. Prathama Chaudhuri, Kolkata; Dr. Nirmal Kumar Bera, Siliguri; Dr. S. K.
38
N. Shah et al. / Asian Journal of Psychiatry 20 (2016) 32–38
Das Slace Clinic, Bhubaneswar; Dr. Debashis Chattererje, Kolkata; Dr. Prosenjit Ghosh, Kolkata; Dr. Rajesh Nagpal, New Delhi; Dr.nSandeep Vohra, New Delhi; Dr. Vimal Kumar; Delhi; Dr. Aneesh Baweja, New Delhi; Dr. Manaswi Gautam, Jaipur; Dr. Ashwani Kumar Santulan, New Delhi; Dr. Sunil Awana, Delhi; Dr. P.S. Das Medicare Centre, Noida; Dr. Ranjive Mahajan, Ludhiana; Dr. S. Nambi, Chennai; Dr. S. Vijayakumar, Chennai; Dr. G.Prasad Rao, Hyderabad; Dr. M. S. Reddy, Hyderabad; Dr. R. Mahesh, Bangalore; Dr. P. N. Suresh Kumar, Kerala; Dr. K. Selvaraj, Coimbatore; Dr. C. Ramasubramanian, Madurai; Dr. Sameer M, Kerala; Dr. Nilesh Shah, Mumbai; Dr. Sandeep Jadhav, Kalyan; Dr. Paresh Lakdawala, Mumbai; Dr. Yusuf Matcheswala, Mumbai; Dr. Sanjay Kumavat, Thane; Dr. Bharat Shah, Chembur; Dr. P.C.Shastri, Mumbai; Dr. B S V Prasad Nashik; Dr. Raman Girotra, Gurgaon; Dr. Samyak Jain, Meerut; Dr. Roop Sidana, Sriganganagar; Dr. Suresh Ninan, Kottayam; Dr. Sailaja Ramkumar, Thrissur; Dr. K. K. Praveen, Thrissur; Dr. Pannerselvan, Tiruelveli; Dr. Gautam Amin Vadodara; Dr. Shailesh Pangaonkar, Nagpur; Dr. Ravi Shankar Krishna, Coimbatore; Dr. Ashit Sheth, Mumbai; Dr. V. George Reddy, Hyderabad. References Andreasen, N.C., Black, D.W., 2006. Introductory Textbook of Psychiatry, fourth ed. American Psychiatric Publishing Inc., Washington, DC. Bipolar Disorder in Adults. 2012. Available at http://www.nimh.nih.gov/health/ publications/bipolar-disorder-in-adults/index.shtmlhttp://www.nimh.nih.gov/ health/publications/bipolar-disorder-in-adults/index.shtml. Accessed on 15/2/ 2016. Bowden, C.L., Brugger, A.M., Swann, A.C., Calabrese, J.R., Janicak, P.G., Petty, F., Dilsaver, S.C., Davis, J.M., Rush, A.J., Small, J.G., et al., 1994. Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. JAMA 271, 918–924. Bowden, C.L., Swann, A.C., Calabrese, J.R., Rubenfaer, L.M., Wozniak, P.J., Collins, M.A., Abi-Saab, W., Saltarelli, M., 2006. A randomized, placebo-controlled, multicenter study of divalproex sodium extended release in the treatment of acute mania. J. Clin. Psychiatry 67, 1501–1510. Bowden, C., Gogus, A., Grunze, H., Haggstrom, L., Rybakowski, J., Vieta, E., 2008. A 12week, open, randomized trial comparing sodium valproate to lithium in patients with bipolar I disorder suffering from a manic episode. Int. Clin. Psychopharmacol. 23, 254–262. Bowden, C.L., Mosolov, S., Hranov, L., Chen, E., Habil, H., Kongsakon, R., Manfredi, R., Lin, H.N., 2010. Efficacy of valproate versus lithium in mania or mixed mania: a randomized, open 12-week trial. Int. Clin. Psychopharmacol. 25, 60–67. Bowden, C.L., 2000. The ability of lithium and other mood stabilizers to decrease suicide risk and prevent relapse. Curr. Psychiatry Rep. 2, 490–494. Busner, J., Targum, S.D., 2007. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont (Pa.: Township)) 4, 28–37. Chopra, M.P., Kumar, K.V., Jain, S., Murthy, R.S., 2010. Psycho-social outcomes for persons with bipolar-I disorder: eight-year follow-up of a rural cohort from south India. Asian J. Psychiatr. 3, 55–59. Cipriani, A., Reid, K., Young, A.H., Macritchie, K., Geddes, J., 2013. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst. Rev. 10, Cd003196. Dilsaver, S.C., 2011. An estimate of the minimum economic burden of bipolar I and II disorders in the United States: 2009. J. Affect. Disord. 129, 79–83. Geller, B., Luby, J.L., Joshi, P., Wagner, K.D., Emslie, G., Walkup, J.T., Axelson, D.A., Bolhofner, K., Robb, A., Wolf, D.V., Riddle, M.A., Birmaher, B., Nusrat, N., Ryan, N.D., Vitiello, B., Tillman, R., Lavori, P., 2012. A randomized controlled trial of risperidone, lithium, or divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. Arch. Gen. Psychiatry 69, 515–528. Ghaemi, S.N., Goodwin, F.K., 2001. Long-term naturalistic treatment of depressive symptoms in bipolar illness with divalproex vs. lithium in the setting of minimal antidepressant use. J. Affect. Disord. 65, 281–287. Goodwin, G.M., 2009. Evidence-based guidelines for treating bipolar disorder: revised second edition—recommendations from the British Association for Psychopharmacology. J. Psychopharmacol. (Oxford, England) 23, 346–388.
Grant, B.F., Stinson, F.S., Hasin, D.S., Dawson, D.A., Chou, S.P., Ruan, W.J., Huang, B., 2005. Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J. Clin. Psychiatry 66, 1205–1215. Grunze, H., Vieta, E., Goodwin, G.M., Bowden, C., Licht, R.W., Moller, H.J., Kasper, S., 2010. The world federation of societies of biological psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2010 on the treatment of acute bipolar depression. World J. Biol. Psychiatry 11, 81–109. Gyulai, L., Bowden, C.L., McElroy, S.L., Calabrese, J.R., Petty, F., Swann, A.C., Chou, J.C., Wassef, A., Risch, C.S., Hirschfeld, R.M., Nemeroff, C.B., Keck Jr., P.E., Evans, D.L., Wozniak, P.J., 2003. Maintenance efficacy of divalproex in the prevention of bipolar depression. Neuropsychopharmacology 28, 1374–1382. Hasnain, M., Vieweg, W.V., Hollett, B., 2012. Weight gain and glucose dysregulation with second-generation antipsychotics and antidepressants: a review for primary care physicians. Postgrad. Med. 124, 154–167. Hirschfeld, R.M., Williams, J.B., Spitzer, R.L., Calabrese, J.R., Flynn, L., Keck Jr., P.E., Lewis, L., McElroy, S.L., Post, R.M., Rapport, D.J., Russell, J.M., Sachs, G.S., Zajecka, J., 2000. Development and Validation of A Screening Instrument for Bipolar Spectrum Disorder: The Mood Disorder Questionnaire. Hirschfeld, R., Bowden, C.L., Gitlin, M.J., Keck, P.E., Suppes, T., Thase, M.E., Perlis, R.H., 2002. Practice guideline for the treatment of patients with bipolar disorder. American Psychiatric Association, Arlington, VA. Horne, R.L., Cunanan, C., 2003. Safety and efficacy of switching psychiatric patients from a delayed-release to an extended-release formulation of divalproex sodium. J. Clin. Psychopharmacol. 23, 176–181. Maji, K.R., Sood, M., Sagar, R., Khandelwal, S.K., 2012. A follow-up study of family burden in patients with bipolar affective disorder. Int. J. Soc. Psychiatry 58, 217–223. Merikangas, K.R., Jin, R., He, J.P., Kessler, R.C., Lee, S., Sampson, N.A., Viana, M.C., Andrade, L.H., Hu, C., Karam, E.G., Ladea, M., Medina-Mora, M.E., Ono, Y., PosadaVilla, J., Sagar, R., Wells, J.E., Zarkov, Z., 2011. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch. Gen. Psychiatry 68, 241–251. Mosolov, S.N., Kostiukova, E.G., Kapiletti, S.G., Belen’kaia, D.V., Shafarenko, A.A., Fedotov, D.D., 2009. [Open randomized comparative twelve-week study of lithium and valproate in manic episode]. Zh. Nevrol. Psikhiatr. Im. S. S. Korsakova 109, 47–52. Muzina, D.J., Gao, K., Kemp, D.E., Khalife, S., Ganocy, S.J., Chan, P.K., Serrano, M.B., Conroy, C.M., Calabrese, J.R., 2011. Acute efficacy of divalproex sodium versus placebo in mood stabilizer-naive bipolar I or II depression: a double-blind, randomized, placebo-controlled trial. J. Clin. Psychiatry 72, 813–819. Patel, N.C., Patrick, D.M., Youngstrom, E.A., Strakowski, S.M., Delbello, M.P., 2007. Response and remission in adolescent mania: signal detection analyses of the young mania rating scale. J. Am. Acad. Child Adolesc. Psychiatry 46, 628–635. Pavuluri, M.N., Henry, D.B., Carbray, J.A., Naylor, M.W., Janicak, P.G., 2005. Divalproex sodium for pediatric mixed mania: a 6-month prospective trial. Bipolar Disord. 7, 266–273. Redden, L., DelBello, M., Wagner, K.D., Wilens, T.E., Malhotra, S., Wozniak, P., Vigna, N.V., Greco, N.t., Kovacs, X., Abi-Saab, W., Saltarelli, M., 2009. Long-term safety of divalproex sodium extended-release in children and adolescents with bipolar I disorder. J. Child Adolesc. Psychopharmacol. 19, 83–89. Sharma, V., Yatham, L.N., Haslam, D.R., Silverstone, P.H., Parikh, S.V., Matte, R., Kutcher, S.P., Kusumakar, V., 1997. Continuation and prophylactic treatment of bipolar disorder. Can. J. Psychiatry 42, 92S–100S, Revue canadienne de psychiatrie. Spearing, M.K., Post, R.M., Leverich, G.S., Brandt, D., Nolen, W., 1997. Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP. Psychiatry Res. 73, 159–171. Stoner, S.C., Dahmen, M.M., 2007. Extended-release divalproex in bipolar and other psychiatric disorders: a comprehensive review. Neuropsychiatr. Dis. Treat. 3, 839–846. Yatham, L.N., Kennedy, S.H., Schaffer, A., Parikh, S.V., Beaulieu, S., O’Donovan, C., MacQueen, G., McIntyre, R.S., Sharma, V., Ravindran, A., Young, L.T., Young, A.H., Alda, M., Milev, R., Vieta, E., Calabrese, J.R., Berk, M., Ha, K., Kapczinski, F., 2009. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009. Bipolar Disord. 11, 225–255. Zajecka, J.M., Weisler, R., Sachs, G., Swann, A.C., Wozniak, P., Sommerville, K.W., 2002. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J. Clin. Psychiatry 63, 1148–1155.
Contents lists available at ScienceDirect
Asian Journal of Psychiatry journal homepage: www.elsevier.com/locate/ajp
Safety and effectiveness of divalproex sodium extended release containing regimen in Indian patients with bipolar I disorder in continuation phase: Results of EASED registry Nilesh Shah a,*, M.S. Reddy b, Sandeep Vohra c, Uday Chaudhuri d, Senthilnathan Mohanasundaram e a
L. T. M. Medical College and General Hospital, Mumbai, India Asha Bipolar Clinic, Asha Hospital, Hyderabad, India c Indraprastha Apollo Hospitals, New Delhi, India d Gaurinath Shastri Memorial Clinic, Kolkata, India e Sanofi, Mumbai, India b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 13 April 2015 Received in revised form 25 November 2015 Accepted 29 November 2015
The study was conducted to evaluate the safety and effectiveness of divalproex sodium XR containing regimen in patients with bipolar disorder (BPD) who are in continuation phase. It was an open-label, prospective, observational study conducted from July 2010 to December 2011 at 48 sites across India. Adult patients with bipolar I disorder of manic or mixed type fulfilling the DSM-IV criteria and who were in the continuation phase were included. Safety (primary outcome) was assessed by incidence of treatment emergent adverse events (AEs). Effectiveness (secondary outcome), was evaluated by proportion of patients who did not have a relapse, change in Clinical Global Impression Score-BP versionSeverity of Illness (CGI-BP) and Young’s Mania Rating Scale (YMRS) score. Data was recorded at three visits: visit-1 (baseline), visit-2 (end of 2 months 7 days) and visit-3 (end of 4 months 14 days), and summarised using descriptive statistics. p < 0.05 was considered statistically significant. A total of 489 and 468 patients were included in the safety and effectiveness analyses, respectively. Of the 66 AEs reported, 57 (89.0%) were mild and 7 (10.9%) were moderate (data missing for 2 events). In total, 75.0% (48/64) of the AEs were related to the study drug. No serious AEs reported (N = 64). No relapse observed in 93.3% of patients. There was a significant (p < 0.0001) reduction in the YMRS and CGI-BP scores from baseline to visit-3. Our study confirms the results of earlier studies in terms of good tolerability and effectiveness of divalproex sodium XR containing regimen in this study population. ß 2015 Elsevier B.V. All rights reserved.
Keywords: Bipolar disorder Valproic acid Depression Mania Safety
1. Introduction Bipolar disorder (BPD) causes unusual shifts in mood and is characterised by transition between depression and mania that affects one’s ability to function (Hirschfeld et al., 2000). The National Comorbidity Study reported a lifetime prevalence of nearly 4.0% for BPD patients worldwide (Andreasen and Black, 2006). Prevalence of 12-month and lifetime Diagnostic and Statistical Manual of Mental Disorder (DSM)—IV bipolar I disorder in U.S. population was 2.0% (95% confidence interval [CI] = 1.82 to 2.18) and 3.3% (95% CI = 2.76 to 3.84), respectively (Grant et al.,
* Corresponding author. Tel.: +91 022 24011984. E-mail address: [email protected] (N. Shah). http://dx.doi.org/10.1016/j.ajp.2015.11.009 1876-2018/ß 2015 Elsevier B.V. All rights reserved.
2005). The WHO World Mental Health survey data shows a 0.1% lifetime as well as 12-month prevalence of Bipolar Spectrum in India (Merikangas et al., 2011). However, BPDs, including both bipolar disorder I and II, are frequently not recognised, and thus remain undiagnosed and untreated (Hirschfeld et al., 2000). BPD imposes a significant economic burden on patients, their families and society as a whole (Dilsaver, 2011). Although there is lack of data on economic burden of BPD in India in published literature, it is likely to be significant. Additionally, patients and their families face significant social and interpersonal burden due to BPD. In a survey conducted in India, more than 90% of family members of patients with BPD reported care-related burden in the absence of clinical interventions (Maji et al., 2012). Similarly, half of the BPD patients showed negative outcomes with difficulties in inter-personal relationships (Chopra et al., 2010).
N. Shah et al. / Asian Journal of Psychiatry 20 (2016) 32–38
Several therapeutic modalities have been recommended for the treatment of BPD. Mood stabilisers, namely, lithium and divalproex are useful in preventing relapse in BPD (Bowden, 2000). Divalproex sodium, an anticonvulsant and mood stabiliser, is widely prescribed to treat BPD as well. Current guidelines recommend valproate (either divalproex or other formulations) as monotherapy or combination therapy with other agents as firstline or second-line treatment for bipolar depression (Goodwin, 2009; Grunze et al., 2010; Yatham et al., 2009). In fact, along with lithium, divalproex sodium or valproic acid is the most commonly prescribed medication for patients with Bipolar Disorder (2012). Lithium and valproate have also been used for the maintenance therapy in BPD (Hirschfeld et al., 2002). A randomised placebocontrolled multicentre study of divalproex sodium extended release (XR) in patients hospitalised for acute mania showed that it was safe and well-tolerated for the treatment of manic episodes (Bowden et al., 2006). A study which compared the efficacy of divalproex, lithium, and placebo in patients with bipolar I disorder demonstrated that divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse, particularly in patients with manic episodes (Gyulai et al., 2003). Similarly, higher response rates (Bowden et al., 2010) and greater remission rates (Bowden et al., 2008) have been seen with sodium valproate when compared to lithium in BPD patients suffering from manic episodes. A 12-week randomised, doubleblind, parallel group study on BPD patients showed that divalproex sodium was associated with a better adverse event (AE) profile and significantly less weight gain when compared to olanzapine (Zajecka et al., 2002). In a recent review by Cochrane group that included 6 randomised controlled trials comparing valproate with placebo, lithium, olazapine and lithium plus valproate combination, no difference in efficacy was found between valproate and lithium (Relative risk [RR] 1.02, 95% CI 0.87 to 1.20) though valproate group had fewer participants dropping out of treatment for any cause when compared with placebo or lithium (RR 0.82, 95% CI 0.71 to 0.95 and RR 0.87, 95% CI 0.77 to 0.98, respectively) (Cipriani et al., 2013). While there are international guidelines about appropriate therapeutic management of BPD, they are predominantly based on evidence gathered from large studies based in Western countries. The rational management of BPD in Indian patients is possible only in light of evidence gathered from contemporary clinical practice in India. There is a scarcity of data supporting the effectiveness and safety of divalproex sodium XR during the continuation phase of BPD patients in India. The current study was proposed to evaluate the safety and effectiveness of divalproex sodium XR (Depakote XR1) in patients with BPD and is the first of its kind in India. Primary objective of the study was to evaluate the safety of divalproex sodium XR containing regimen in patients with BPD in continuation phase. Secondary objective of the study was to evaluate the effectiveness of divalproex sodium XR containing regimen in patients with BPD in the continuation phase.
2. Materials and methods The present study was an open-label, single-arm, multicentre, prospective observational study, conducted from July 2010 to December 2011 at 48 sites across India by 48 investigators. The study was conducted according to the guidelines for Good Epidemiology Practice, the principles of Declaration of Helsinki of 1975, as revised in 2000, and in accordance with the local regulations of institutional review board/institutional ethics committee. Written, signed informed consent was obtained from each patient enrolled in the study.
33
Adult patients with bipolar I disorder of manic or mixed type (as per DSM-IV-TR criteria), who were treated for an acute episode and were in the continuation phase (defined as commencing once euthymia and resolution of psychosis have been achieved), (Sharma et al., 1997) and who were, prescribed divalproex sodium XR containing regimen by the investigator, were included in the study. Patients having any other clinically significant psychiatric disorder, cardiovascular, hepatic, neurological, endocrine or other major systemic disease were excluded from the study. Case report forms were used to collect data from source documents (patient file, prescription letters or any other relevant document) at three visits: visit 1 (baseline), visit 2 (end of 2 months 7 days) and visit 3 (end of 4 months 14 days). Demographic features, dose and duration for which divalproex sodium XR was taken, duration of BPD, concomitant medication use, relapse of mania associated with BPD and Clinical Global Impression Score-BP version-Severity of Illness (CGI-BP) and Young’s Mania Rating Scale (YMRS) score were recorded in the case report forms. The total number of AEs reported by patients and the severity, seriousness, and relationship of the AE to the study medication were analysed. Proportion of patients who discontinued study drug at visit 2 and visit 3 and the reasons for discontinuation were documented. Effectiveness of the drug was assessed by measuring the change in CGI-BP and YMRS at visit 2 (end of 2 months 7 days) and visit 3 (end of 4 months 14 days) compared to baseline (visit 1). Proportion of patients experiencing relapse were also recorded. 2.1. Statistical analysis Assuming that 23% of the patients would have shown treatment-emergent AEs, with confidence interval of 90% and precision of 3%, it was estimated that 529 patients would be required for the study. A sample size of 635 was determined for the study assuming a drop out of 20%. All categorical variables were presented as proportions and percentages. Continuous variables were reported as mean with standard deviation. A p-value <0.05 was considered statistically significant. All statistical analyses were carried out using SAS 9.1.3 (SAS Institute Inc., Cary, NC, USA). 3. Results 3.1. Patient disposition and demographics Out of the total 578 patients screened, 489 were included in the safety analyses and 468 were included in the effectiveness analyses; 474 patients completed the study. Patient disposition and the reasons for discontinuation have been summarised in Fig. 1. In the safety analyses set, 345 patients (70.6%) were male and 144 (29.4%, N = 489) were female, with a mean age of 35.6 11.1years. In the effectiveness analysis set, 331 (70.7%, N = 468) patients were male and 137 (29.3%, N = 468) patients were female, with a mean age 35.6 11.0 years. The mean duration of BPD was 69.2 82.2 months and the mean duration of acute episodes was 31 23.7 days. The mean dose of divalproex sodium XR taken was 907.9 316.1 mg/day and 883.5 300.8 mg/day during visit 2 and 3, respectively. Divalproex sodium XR was taken for a mean duration of 65.1 16.0 and 104.5 28.1 days for visit 2 and visit 3, respectively. Olanzapine was the most commonly used concomitant medication at visit 2 [n = 149 (44.6%)] and visit 3 [n = 119 (39.8%)] (Table 1). 3.2. Safety outcomes A total of 66 AEs were observed in 56 patients (11.5%, N = 489) during the study. Most frequently observed AEs were alopecia (2.5%, 12 events in 12 patients) and tremor (1.4%, 8 events in 7
34
N. Shah et al. / Asian Journal of Psychiatry 20 (2016) 32–38
Fig. 1. Patient disposition.
patients). Out of the 66 AEs reported, 57 (89.0%) were mild and 7 (10.9%) were moderate; this data was missing for 2 events. None of the AEs were serious (N = 64 since this data was missing for 2 events). A total of 48 (75.0%; N = 64) AEs were related to the study drug, whereas 16 (25.0%; N = 64) AEs were not related to the study drug; this data was missing for 2 events. Corrective treatment was given to 36 (57.1%; N = 63 since this data was missing for 3 events) patients. Discontinuation of divalproex sodium XR was reported in 4 AEs (6.3%, N = 63 since this data was missing for 3 events); in 2 events (of alopecia), divalproex sodium XR was discontinued permanently and in the other 2 events (1 of alopecia and 1 of headache), it was discontinued temporarily. Most of the AEs (28/62; 45.2%) were resolved, 12 (19.4%, N = 62) were being resolved, and 22 (35.5%, N = 62) did not resolve; this data was missing for 3 events and for 1 event the outcome was unknown. AEs reported during the current study have been summarised in (Table 2). 3.3. Effectiveness outcomes A total of 468 patients were included in the effectiveness analysis. Relapse was observed in 6.7% (n = 31) of the patients. Of the total 31 patients who suffered relapse, 9 suffered from episodes of depression, 14 from episodes of mania and 6 suffered both (data was missing for 2 patients). The summary of relapse associated with BPD and episodes of depression and mania have been listed in (Table 3). There was a significant reduction in the YMRS score (p < 0.0001) (Table 4) and CGI-BP depression, mania as well as overall scores (p < 0.0001) (Table 5). 4. Discussion This study was an open-label, prospective, observational study to estimate the safety and effectiveness of divalproex sodium XR containing regimen in patients with bipolar I disorder who were in the continuation phase. Divalproex sodium XR was well-tolerated with mild (89.0%) and moderate (10.9%) AEs. No serious AEs were reported in the study. No relapse was observed in 93.3% of the patients during the study. The change in the YMRS score and CGIBP score from baseline to visit 3 (end of 4 months 14 days) was statistically significant indicating that divalproex sodium XR containing regimen reduced the severity of illness and was effective in patients with bipolar I disorder. Incidence of weight gain, glucose dysregulation and metabolic changes are associated with BPD patients treated with antipsychotics
and antidepressants drugs (Hasnain et al., 2012). Weight gain and increased body mass index are the most common AEs related to divalproex sodium XR therapy (Bowden et al., 2006; Geller et al., 2012; Redden et al., 2009; Zajecka et al., 2002). In the current study, only 1.4% of patients with BPD experienced weight gain with divalproex sodium XR treatment. The overall incidence of AEs was low in the current study when compared with a previous randomised placebo-controlled study on divalproex sodium XR treatment (11.5%, N = 489 vs. 84%, N = 192), which reported somnolence (33%), nausea (28%) and dyspepsia (26%) as the most common AEs (Bowden et al., 2006). In another randomised study on divalproex sodium XR treatment, the reported AE rate for somnolence was 29% and rhinitis was 3% (Zajecka et al., 2002). In the current study, alopecia (2.5%, 12 events in 12 patients) and tremor (1.4%, 8 events in 7 patients) were the most common AEs, and somnolence occurred in only 1.4% (7 events in 7 patients), nausea in 0.4% (2 events in 2 patients), and rhinitis in 0.2% (1 event in 1 patient) of patients. Also, the documented AEs reflect the spectrum of complaints usually observed with divalproex sodium XR treatment. The minor side effects of divalproex sodium like sedation or gastrointestinal distress are common initially and typically resolve with continued treatment or dose adjustment (Hirschfeld et al., 2002). No AEs were reported by 88.5% of the study population, indicating that divalproex sodium XR was well-tolerated and safe in the study population. Due to the occurrence of AEs, out of 4 patients in whom the study drug was discontinued, 2 patients withdrew from the study, and in 6.3% (4/63) of the events, the study drug was discontinued. Similarly lower discontinuation rates, particularly related to AEs were reported in a previous study i.e. 26% and 6% for lithium and valproate, respectively (Bowden et al., 2008). The data from the present study is also consistent with the results of another 3 week study for acute mania in which divalproex sodium formulation was better tolerated and had limited discontinuations when compared to lithium (Bowden et al., 1994). Dose escalation in extended release of divalproex sodium is well tolerated in the patients with BPD (Stoner and Dahmen, 2007). An open-label study (Horne and Cunanan, 2003) which evaluated the safety and efficacy of divalproex sodium in switching patients from delayed release to extended release suggested that divalproex sodium XR was better tolerated and equally effective in treating patients with psychiatric illness. Moreover divalproex sodium XR in once daily dosage regimen improved patient compliance.
Table 1 Summary of concomitant medication. Visit 3
334
299
Drug
n (%)
Alprazolam Amisulpride Amitriptyline Aripiprazole Atenolol Becosules Benfotiamine Biotin Carbamazepine Chlordiazepoxide Chlorpromazine Clonazepam Clozapine Domperidone Dosulepin Escitalopram Fluoxetine Fluphenazine Fluvoxamine Glimepiride Haloperidol Lactulose Lamotrigine Levothyroxine Sodium Lithium Lithium Carbonate Lorazepam Metformin Nitrazepam Olanzapine Oxcarbazepine Paliperidone Paracetamol Pioglitazone Pramipexole Promethazine Propranolol Psycholeptics and psychoanaleptics in combination Quetiapine Ranitidine Risperidone Sertraline Topiramate Trifluoperazine Trihexyphenidyl Valproate Semisodium
1(0.3) 10(3.0) 2(0.6) 6(1.8) 1(0.3) 1(0.3) 1(0.3) 2(0.6) 5(1.5) 2(0.6) 7(2.1) 59(17.7) 9(2.7) 1(0.3) 3(0.9) 5(1.5) 2(0.6) 2(0.6) 2(0.6) 1(0.3) 32(9.6) 1(0.3) 7(2.1) 1(0.3) 68(20.4) 12(3.6) 48(14.4) 2(0.6) 6(1.8%) 149(44.6) 8(2.4) 1(0.3) 0 1(0.3) 1(0.3) 2(0.6) 3(0.9) 4(1.2)
1.0 175.0 (108.64) 7.5 (3.54) 10.0 (3.16) 100.0 – 100.0 10.0 360.0 (167.33) 2.5 (3.5285) 101.5 (148.85) 2.2 (4.51) 69.4 (41.04) 0.0 25.1 (43.26) 6.0 (5.47) 20.0 (0.00) 25.0 35.0 (21.21) 1.5 8.8 (6.50) – 146.4 (68.36) 50.0 724.3 (232.82) 908.3 (242.930) 1.9 (1.00) 875.0 (883.88) 10.0 (0.00) 9.7 (6.25) 637.5 (250.36) 9.0 – 15.0 0.130 17.5 (10.61) 30.0 (17.32) 10.0 (6.12)
51(15.3) 2(0.6) 64(19.2) 1(0.3) 4(1.2) 5(1.5) 50(15.0) 39(11.7)
234.3 (134.62) 300.0 (0.00) 5.516 (13.50) 100.0 37.5 (14.4338) 10.0 (5.00) 3.1 (1.69) 843.8 (251.20)
Dose (mg/day) Mean (SD)
Duration (days) Median (min-max) 1.0 (1.00–1.00) 200.0 (0.05–300.00) 7.5 (5.00–10.00) 10.0 (5.00–15.00) 100.0 (100.00–100.00) – 100.0 (100.00–100.00) 10.0 (10.00–10.00) 400.0 (200.00–600.00) 2.5 (0.01–5.00) 10.000 (0.01–400.00) 1.0(0.00–25.00) 50.0 (25.00–150.00) 0.0 (0.02–0.02) 0.1 (0.08–75.00) 10.0 (0.01–10.00) 20.0 (20.00–20.00) 25.0 (25.00–25.00) 35.0 (20.00–50.00) 1.5 (1.50–1.50) 7.5 (0.00–30.00) – 200.0 (50.00–200.00) 50.0 (50.00–50.00) 900.0 (0.80–1350.00) 900.0 (600.00–1500.00) 2.0 (0.00–6.00) 875.0 (250.00–1500.00) 10.0 (10.00–10.00) 10.0 (0.01–30.00) 600.0 (300.00–1200.00) 9.0 (9.00–9.00) – 15.0 (15.00–15.00) 0.1 (0.13–0.13) 17.5 (10.00–25.00) 40.0 (10.00–40.00) 10.0 (0.01–15.00)
200.0 300.0 3.0 100.0 37.5 10.0 3.0 1000.0
(0.10–600.00) (300.00–300.00) (0.00–100.00) (100.00–100.00) (25.00–50.00) (5.00–15.00) (0.00–8.00) (500.00–1500.00)
n (%)
Mean (SD)
Median (min-max)
61.0 267.9 (297.22) 69.5 (12.02) 279.8 (435.50) 152.0 30.0 92.0 32.5 (3.54) 71.0 (22.36) 202.0 (147.08) 240.6(250.61) 128.5 (201.96) 200.3 (240.83) 92.0 101.7 (63.74) 99.2 (101.95) 45.5 (21.92) 328.0 (197.99) 45.5 (21.92) 77.0 538.4 (1348.80) 3.0 235.7 (173.23) 51.0 729.0 (1258.61) 468.4 (294.33) 160.5 (258.90) 3165.5 (3874.24) 721.0 (766.60) 410.5 (1852.20) 158.3 (93.10) 287.0 – 77.0 61.0 61.0 (0.00) 152.0 (185.11) 60.8 (43.67)
61.0 122.0 69.5 78.0 152.0 30.0 92.0 32.5 61.0 202.0 152.0 61.0 109.0 92.0 123.0 45.0 45.5 328.0 45.5 77.0 146.0 3.0 244.0 51.0 183.0 477.5 63.0 3165.5 487.0 81.0 137.0 287.0 – 77.0 61.0 61.0 61.0 30.0
211.7 38.0 268.0 244.0 76.3 456.6 216.2 119.7
(231.81) (32.53) (508.07) (39.89) (800.59) (341.46) (170.48)
77.0 38.0 82.0 244.0 76.0 122.0 93.5 61.0
(61–61) (61–791) (61–78) (61–1157) (152–152) (30–30) (92–92) (30–35) (61–111) (98–306) (91–791) (15–1157) (61–731) (92–92) (30–152) (30–268) (30–61) (188–468) (30–61) (77–77) (10–7366) (3–3) (38–426) (51–51) (30–7366) (61–974) (5–1157) (426–5905) (91–2043) (4–22) (69–335) (287–287) (77–77) (61–61) (61–61) (30–365) (30–123)
(30–980) (15–61) (30–3044) (244–244) (30–123) (61–1887) (10–1522) (28–974)
Dose (mg/day)
Duration (days)
Mean (SD)
Median (min-max)
Mean (SD)
Median (min-max)
1(0.3) 11(3.7) 2(0.7) 5(1.7) 1(0.3) 0 1(0.3) 1(0.3) 5(1.7) 2(0.7) 4(1.3) 46(15.4) 7(2.3) 1(0.3) 3(1.0) 8(2.7) 0 2(0.7) 0 0 20(6.7) 1(0.3) 7(2.3) 1(0.3) 59(19.7) 11(3.7) 30 (10.0) 2(0.7) 6(2.0) 119(39.8) 8(2.7) 1(0.3) 3(1.0) 0 2(0.7) 1(0.3) 4(1.3) 2(0.7)
25.0 168.2 (105.52) 5.0 (0.00) 12.0 (2.74) 100.0 – 0.10 0.0 240.0 (114.02) 0.1 (0.06) 137.5 (188.74) 3.4 (9.80) 128.6 (85.91) 0.0 25.1 (43.26) 6.3 (5.7473) – 25.0 (0.00) – – 9.5 (7.05) – 164.29 (62.68) 50.0 727.9 (229.52) 825.5 (364.87) 2.2 (1.12) 875.00(883.88) 10.0 (0.00) 9.0 (6.73) 637.5 (250.36) 9.0 1166.6 (577.350 – 0.1 (0.00) 25.0 25.0 (12.91) 0.0 (0.00)
25.0 (25.00–25.00) 200.0 (0.05–300.00) 5.0 (5.00–5.00) 10.0 (10.00–15.00) 100.0 (100.00–100.00) – 0.1 (0.10–0.10) 0.0 (0.01–0.01) 200.0 (100.00–400.00) 0.06 (0.01–0.10) 75.005 (0.01–400.00) 1.000 (0.01–62.50) 100.0 (50.00–300.00) 0.0 (0.02–0.02) 0.1 (0.08–75.00) 7.5 (0.01–15.00) – 25.0 (25.00–25.00) – – 10.0 (0.00–30.00) – 200.0 (50.00–200.00) 50.0 (50.00,50.00) 800.0 (0.60–1350.00) 900.0 (80.00–1500.00) 2.0 (1.00–6.00) 875.0 (250.00–1500.00) 10.0 (10.00–10.00) 5.0 (0.01–30.00) 600.0 (300.00–1200.00) 9.0 (9.00–9.00) 1500.0 (500.00–1500.00) – 0.1 (0.13–0.13) 25.0 (25.00–25.00) 25.0 (10.00–40.00) 0.0 (0.01–0.01)
30.0 282.5 (309.62) 131.0 (12.73) 366.8 (484.73) 213.0 – 154.0 61.0 89.4 (63.50) 263.0 (148.49) 391.3 (316.70) 159.4 (223.48) 167.3 (253.22) 155.0 178.7 (38.89) 124.8(104.58) – 388.5 (197.28) – – 722.2 (1616.60) 3.0 295.9 (172.54) 114.0 773.2 (1262.96) 613.4 (520.88) 281.1 (346.10) 3226.5 (3874.24) 771.8 (761.01) 335.8 (571.26) 210.8 (104.45) 344.0 1166.667(577.350 – 61.0 (0.00) 99.0 152.0 (187.74) 199.5 (20.51)
30.0 (30–30) 154.0 (61–852) 131.0 (122–140) 152.0 (61–1218) 213.0 (213–213) – 154.0 (154–154) 61.0 (61–61) 61.0 (61–203) 263.0 (158–368) 277.5 (158–852) 61.0 (30–1218) 61.0 (20–731) 155.0 (155–155) 185.0 (137–214) 132.0 (10–327) – 388.5 (249–528) – – 258.5 (30–7427) 3.0(3–3) 295.0 (101–487) 114.0 (114–114) 254.0 (45–7427) 536.0 (99–1913) 122.0 (61–1218) 3226.5 (487–5966) 548.0 (152–2104) 147.0 (15–3774) 198.0 (63–396) 344.0 (344–344) 3.0 (2–3) – 61.0 (61–61) 99.0 (99–99) 76.0 (30–426) 199.5 (185–214)
45(15.1) 1(0.3) 50(16.7) 1(0.3) 2(0.7) 4(1.3) 35 (11.7) 36(12.0)
238.6 (167.69) 300.00 2.530(1.49) 100.0 37.5 (17.68) 8.8 (4.79) 3.0 (1.56) 784.7 (247.51)
200.0 300.0 2.0 100.0 37.5 7.5 2.0 1000.0
(0.10–600.00) (300.00–300.00) (0.00–6.00) (100.00–100.00) (25.00–50.00) (5.00–15.00) (0.00–8.00) (250.00–1000.00)
277.0 76.0 427.1 304.0 162.5 570.8 313.7 178.9
(268.73) (768.66) (187.38) (920.96) (405.76) (272.56)
155.0 76.0 152.0 304.0 162.5 137.0 183.0 61.0
N. Shah et al. / Asian Journal of Psychiatry 20 (2016) 32–38
Visit 2 (N = 488) No. patients on concomitant medication (N)
(2–1049) (76–76) (30–3805) (304–304) (30–295) (61–1948) (30–1583) (30–1157) 35
N. Shah et al. / Asian Journal of Psychiatry 20 (2016) 32–38
(213–213)
(313–313) (154–396) (30–149)
313.0 244.0 61.0 – 213.0 (200.00–200.00)
313.0 264.7 (122.32) 80.0 (61.73) – 213.0 (225.00–225.00) (0.02–80.00) (5.00–6.25)
225.0 20.0 5.0 – 200.0 225.0 33.3 (41.63) 5.4 (0.72) – 200.0 1(0.3) 3(1.0) 3(1.0) 0 1(0.3) (253–253) (92–335) (61–92) (30–30) 253.0 183.0 61.0 30.0 – 253.0 203.3(122.77) 71.3(17.90) 30.0 – 225.0 (225.00–225.00) 20.0 (0.02–80.00) 10.0 (5.00–12.50) – – 225.0 33.3 (41.63) 9.2 (3.82) – – 1(0.3) 3(0.9) 3(0.9) 1(0.3) 0
n (%) Drug
Venlafaxine Ziprasidone Zolpidem Zuclopenthixol Zuclopenthixol Decanoate
Duration (days) Dose (mg/day) n (%) Duration (days)
Mean (SD) Mean (SD)
334
Visit 2 (N = 488) Table 1 (Continued )
No. patients on concomitant medication (N)
Median (min-max) Dose (mg/day)
Median (min-max)
299
Visit 3
Mean (SD)
Median (min-max)
Mean (SD)
Median (min-max)
36
Table 2 Adverse events related with the study drug (N = 489). Adverse events
No. of events
Patients, n (%)
Alopecia Tremors Somnolence Weight gain Headache Constipation Gastritis Nausea Peripheral edema Pyrexia Appetite disorder Increased appetite Dizziness Vomiting Insomnia Amenorrhea Rhinitis Upper respiratory tract infection
12 8 7 7 6 5 4 2 2 2 2 2 2 1 1 1 1 1
12 7 7 7 5 5 4 2 2 2 2 2 2 1 1 1 1 1
(2.5) (1.4) (1.4) (1.4) (1.0) (1.0) (0.8) (0.4) (0.4) (0.4) (0.4) (0.4) (0.4) (0.2) (0.2) (0.2) (0.2) (0.2)
Table 3 Summary of relapse associated with bipolar disorder. Variables
Visit 2 (N = 467)
Visit 3 (N = 463)
Overall (N = 468)
Total patients analysed for relapse associated with BPD (N) Yes, n (%) No, n (%) Data missing, (n) Total number of relapse, (n) Mean (SD) Median Min, Max Missing, (n)
452
447
463
22 (4.9) 430 (95.1) 15 22 1.8 (1.97) 1.0 1, 10 0
22 (4.9) 425 (95.1) 16 20 1.9 (2.05) 1.0 1, 10 2
31(6.7) 432 (93.3) 5 29 2.7 (3.71) 1.0 1, 20 2
BPD = Bipolar disorder patients, SD = Standard deviation.
Divalproex sodium XR therapy provided reliable anti-manic effect in real-life practice with no relapse in 93.3% of patients in the current study. YMRS scores are often utilised in defining response in patients even if definitive remission is not seen (Patel et al., 2007). In the current study, there was a significant reduction in the mean YMRS score ( 4.5 6.2) from baseline to visit 3, which indicated that patients showed response to divalproex sodium XR administration. This is in line with an earlier study reporting significant reduction in the mean YMRS scores (mean change: 12.4 8.07) with divalproex sodium XR (Redden et al., 2009). In a randomised study, 51.7% of patients in the lithium group showed response to treatment (50% reduction in YMRS scores) in comparison to 56.7% of patients in valproate sodium group (Mosolov et al., 2009). In a comparative open-label 3-month study of lithium and sodium valproate, higher remission rates were reported in sodium valproate group than in lithium group (72.3% vs. 66.5%) (Bowden et al., 2008)). In another placebo-controlled trial, response rates of 48% were seen in divalproex sodium XR group when compared to 34% in placebo group (Bowden et al., 2006). The CGI scale is used to quantify and track patient progress and treatment response over time (Busner and Targum, 2007). The CGIBP provides an accurate and reliable global assessment of illness, severity and degree of improvement occurring in mania, depression and in the overall illness on a given treatment (Spearing et al., 1997). In an earlier study, CGI-BP was measured as primary outcome where divalproex demonstrated long-term antidepressant effects in patients with BPD (Ghaemi and Goodwin, 2001). There was significant reduction in CGI-BP scores in the current study which suggests consistent improvements in both mania and depression status of patients. On the contrary, data from a recent study on acute efficacy of divalproex sodium XR on mood stabiliser
N. Shah et al. / Asian Journal of Psychiatry 20 (2016) 32–38
37
Table 4 Change from baseline in Young’s Mania Rating Scale at Visit 2 and 3 for overall patients. Descriptive statistics
Visit 1 (N = 468)
Visit 2 (N = 467)
Total number (N) Mean (SD) Median Min, Max Missing
468 6.9 (7.4) 6 0, 51 0
465 4.0 (4.8) 3 0, 38 2
Change at visit 2 from baseline 465 3.0 (4.9) 2 13, 45 0
p-Value
Visit 3 (N = 463)
Change at visit 3 from baseline
p-Value
<0.0001a
456 2.5 (3.6) 2 0, 29 7
456 4.5 (6.15) 3 3, 48 0
<0.0001a
a Wilcoxon Signed Rank Test is used to test the mean difference in scores between the baseline and the two visits; test was done at 5% level of significance; p 0.05 indicates significance. SD = Standard deviation.
Table 5 Change from baseline in Clinical Global Impression Score—BP version-Severity of Illness at visit 2 and 3. Severity of Illness
Visit 1 (N = 468) Visit 2 (N = 467) Change at visit 2 from baseline p-Value
461 Mania, (n) Mean (SD) 2.1 (1.33) Depression, (n) 408 Mean (SD) 1.3 (0.89) Overall Bipolar illness, (n) 442 Mean (SD) 2.0 (1.27)
457 1.7 (1.02) 409 1.1 (0.54) 440 1.7 (1.13)
457 0.5 (1.03) 402 0.2 (0.93) 437 0.3 (1.01)
Visit 3 (N = 463) Change at visit 3 from baseline p-Value
442 1.5 (0.93) 401 <0.0001 1.1 (0.66) 442 <0.0001 1.5 (0.99) <0.0001
442 0.7 (1.10) 394 0.2 (1.03) 429 0.6 (1.06)
<0.0001 <0.0001 <0.0001
Wilcoxon Signed Rank Test is used to test the mean difference in scores between the baseline and the two visits; test was done at 5% level of significance; p 0.05 indicates significance; CGI-BP score was calculated as 1 = Normal/not ill, 2 = Minimally ill, 3 = Mildly ill, 4 = Moderately ill, 5 = Markedly ill, 6 = Severely ill, 7 = Very severely ill. SD = Standard deviation.
naı¨ve patients with BPD showed no significant change in the CGI scores (Muzina et al., 2011). Significant improvements from baseline in YMRS and CGI-BP score were also observed with divalproex sodium in the treatment of paediatric mixed mania over a 6-month period (Pavuluri et al., 2005). BPD remains a largely unexplored issue in the realm of psychiatric illnesses in India. Nonetheless, the burden that BPD imposes on patients can clearly be surmised from the current literature on the subject, however scant. The availability of effective therapeutic options is essential to addressing the issues faced by people with BPD. The current study is the first of its kind in addressing the question of safety and effectiveness of divalproex sodium XR, in Indian patients. 4.1. Study limitations The results must be interpreted with caution as the study did not meet the target sample size recruitment. Additionally, there were no multivariate/stratified analyses to rule out the effect of confounders like concomitant medications. Depression was not assessed by a symptom driven scale like HAM-D or equivalent and the follow-up period of 4 months may be considered short to evaluate the prophylactic efficacy of a mood stabiliser. The openlabel, single-arm, observational nature of the study could be a source for potential bias (like selection bias). Nonetheless, this study establishes the evidence for further investigation of divalproex sodium XR in randomised clinical trials as well as observational registries in India. In summary, subjects with bipolar I disorder in continuation phase treated with divalproex containing regimen, showed improvements in YMRS and CGI-BP score indicating a reduction in the severity of the illness. Majority of the patients responded to divalproex sodium XR during the treatment period. Relapse associated with BPD was not seen in majority of patients. Divalproex sodium XR was well-tolerated with mild and moderate AEs. No serious AEs reported. The study results correspond well with other studies where efficacy and good tolerability of divalproex sodium in the treatment and maintenance of acute and mixed mania is established in short-term/placebo-controlled/ parallel-group trials, with effectiveness comparable to other mood
stabilizing agents like lithium. Thus, it can be concluded that divalproex sodium XR containing regimen confirms the results of earlier studies in terms of good tolerability and effectiveness in Indian patients with bipolar I disorder in continuation phase. Conflict of interest statement Vohra S., Chaudhuri U. and Reddy M.S. have been invited speakers in meetings by Sanofi and received honoraria as a consultant. Shah N. has participated as invited faculty in the scientific meetings organised by Sanofi. All authors have received remuneration for the time spent in conducting the study from Sanofi. Mohanasundaram S., is an employee of Sanofi. Funding This study was sponsored by Sanofi (India). Medical writing support for preparing this manuscript was funded by Sanofi (India). Author’s contribution All authors have contributed substantially to the conception and design of the study and the acquisition of data; additionally, they have revised the article critically for important intellectual content and have provided their approval for publication. Acknowledgements The authors acknowledge Jeevan Scientific Technology Limited (Hyderabad, India), and Anahita Gouri and Dr. Alina Gomes of Sanofi (India) for providing writing and editing assistance in developing this manuscript. The authors also thank all the investigators who participated in the study. We would like to thank the following participating physicians who recruited patients—Dr. Debashis Ray, Kolkata; Dr. Partha Dutta, Kolkata; Dr. Amarnath Mallik, Kolkata; Dr. Abhay Kumar Dey, Howrah; Dr. Bijoy Chaudhuri, Guwahati; Dr. Prathama Chaudhuri, Kolkata; Dr. Nirmal Kumar Bera, Siliguri; Dr. S. K.
38
N. Shah et al. / Asian Journal of Psychiatry 20 (2016) 32–38
Das Slace Clinic, Bhubaneswar; Dr. Debashis Chattererje, Kolkata; Dr. Prosenjit Ghosh, Kolkata; Dr. Rajesh Nagpal, New Delhi; Dr.nSandeep Vohra, New Delhi; Dr. Vimal Kumar; Delhi; Dr. Aneesh Baweja, New Delhi; Dr. Manaswi Gautam, Jaipur; Dr. Ashwani Kumar Santulan, New Delhi; Dr. Sunil Awana, Delhi; Dr. P.S. Das Medicare Centre, Noida; Dr. Ranjive Mahajan, Ludhiana; Dr. S. Nambi, Chennai; Dr. S. Vijayakumar, Chennai; Dr. G.Prasad Rao, Hyderabad; Dr. M. S. Reddy, Hyderabad; Dr. R. Mahesh, Bangalore; Dr. P. N. Suresh Kumar, Kerala; Dr. K. Selvaraj, Coimbatore; Dr. C. Ramasubramanian, Madurai; Dr. Sameer M, Kerala; Dr. Nilesh Shah, Mumbai; Dr. Sandeep Jadhav, Kalyan; Dr. Paresh Lakdawala, Mumbai; Dr. Yusuf Matcheswala, Mumbai; Dr. Sanjay Kumavat, Thane; Dr. Bharat Shah, Chembur; Dr. P.C.Shastri, Mumbai; Dr. B S V Prasad Nashik; Dr. Raman Girotra, Gurgaon; Dr. Samyak Jain, Meerut; Dr. Roop Sidana, Sriganganagar; Dr. Suresh Ninan, Kottayam; Dr. Sailaja Ramkumar, Thrissur; Dr. K. K. Praveen, Thrissur; Dr. Pannerselvan, Tiruelveli; Dr. Gautam Amin Vadodara; Dr. Shailesh Pangaonkar, Nagpur; Dr. Ravi Shankar Krishna, Coimbatore; Dr. Ashit Sheth, Mumbai; Dr. V. George Reddy, Hyderabad. References Andreasen, N.C., Black, D.W., 2006. Introductory Textbook of Psychiatry, fourth ed. American Psychiatric Publishing Inc., Washington, DC. Bipolar Disorder in Adults. 2012. Available at http://www.nimh.nih.gov/health/ publications/bipolar-disorder-in-adults/index.shtmlhttp://www.nimh.nih.gov/ health/publications/bipolar-disorder-in-adults/index.shtml. Accessed on 15/2/ 2016. Bowden, C.L., Brugger, A.M., Swann, A.C., Calabrese, J.R., Janicak, P.G., Petty, F., Dilsaver, S.C., Davis, J.M., Rush, A.J., Small, J.G., et al., 1994. Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. JAMA 271, 918–924. Bowden, C.L., Swann, A.C., Calabrese, J.R., Rubenfaer, L.M., Wozniak, P.J., Collins, M.A., Abi-Saab, W., Saltarelli, M., 2006. A randomized, placebo-controlled, multicenter study of divalproex sodium extended release in the treatment of acute mania. J. Clin. Psychiatry 67, 1501–1510. Bowden, C., Gogus, A., Grunze, H., Haggstrom, L., Rybakowski, J., Vieta, E., 2008. A 12week, open, randomized trial comparing sodium valproate to lithium in patients with bipolar I disorder suffering from a manic episode. Int. Clin. Psychopharmacol. 23, 254–262. Bowden, C.L., Mosolov, S., Hranov, L., Chen, E., Habil, H., Kongsakon, R., Manfredi, R., Lin, H.N., 2010. Efficacy of valproate versus lithium in mania or mixed mania: a randomized, open 12-week trial. Int. Clin. Psychopharmacol. 25, 60–67. Bowden, C.L., 2000. The ability of lithium and other mood stabilizers to decrease suicide risk and prevent relapse. Curr. Psychiatry Rep. 2, 490–494. Busner, J., Targum, S.D., 2007. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont (Pa.: Township)) 4, 28–37. Chopra, M.P., Kumar, K.V., Jain, S., Murthy, R.S., 2010. Psycho-social outcomes for persons with bipolar-I disorder: eight-year follow-up of a rural cohort from south India. Asian J. Psychiatr. 3, 55–59. Cipriani, A., Reid, K., Young, A.H., Macritchie, K., Geddes, J., 2013. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst. Rev. 10, Cd003196. Dilsaver, S.C., 2011. An estimate of the minimum economic burden of bipolar I and II disorders in the United States: 2009. J. Affect. Disord. 129, 79–83. Geller, B., Luby, J.L., Joshi, P., Wagner, K.D., Emslie, G., Walkup, J.T., Axelson, D.A., Bolhofner, K., Robb, A., Wolf, D.V., Riddle, M.A., Birmaher, B., Nusrat, N., Ryan, N.D., Vitiello, B., Tillman, R., Lavori, P., 2012. A randomized controlled trial of risperidone, lithium, or divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. Arch. Gen. Psychiatry 69, 515–528. Ghaemi, S.N., Goodwin, F.K., 2001. Long-term naturalistic treatment of depressive symptoms in bipolar illness with divalproex vs. lithium in the setting of minimal antidepressant use. J. Affect. Disord. 65, 281–287. Goodwin, G.M., 2009. Evidence-based guidelines for treating bipolar disorder: revised second edition—recommendations from the British Association for Psychopharmacology. J. Psychopharmacol. (Oxford, England) 23, 346–388.
Grant, B.F., Stinson, F.S., Hasin, D.S., Dawson, D.A., Chou, S.P., Ruan, W.J., Huang, B., 2005. Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J. Clin. Psychiatry 66, 1205–1215. Grunze, H., Vieta, E., Goodwin, G.M., Bowden, C., Licht, R.W., Moller, H.J., Kasper, S., 2010. The world federation of societies of biological psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2010 on the treatment of acute bipolar depression. World J. Biol. Psychiatry 11, 81–109. Gyulai, L., Bowden, C.L., McElroy, S.L., Calabrese, J.R., Petty, F., Swann, A.C., Chou, J.C., Wassef, A., Risch, C.S., Hirschfeld, R.M., Nemeroff, C.B., Keck Jr., P.E., Evans, D.L., Wozniak, P.J., 2003. Maintenance efficacy of divalproex in the prevention of bipolar depression. Neuropsychopharmacology 28, 1374–1382. Hasnain, M., Vieweg, W.V., Hollett, B., 2012. Weight gain and glucose dysregulation with second-generation antipsychotics and antidepressants: a review for primary care physicians. Postgrad. Med. 124, 154–167. Hirschfeld, R.M., Williams, J.B., Spitzer, R.L., Calabrese, J.R., Flynn, L., Keck Jr., P.E., Lewis, L., McElroy, S.L., Post, R.M., Rapport, D.J., Russell, J.M., Sachs, G.S., Zajecka, J., 2000. Development and Validation of A Screening Instrument for Bipolar Spectrum Disorder: The Mood Disorder Questionnaire. Hirschfeld, R., Bowden, C.L., Gitlin, M.J., Keck, P.E., Suppes, T., Thase, M.E., Perlis, R.H., 2002. Practice guideline for the treatment of patients with bipolar disorder. American Psychiatric Association, Arlington, VA. Horne, R.L., Cunanan, C., 2003. Safety and efficacy of switching psychiatric patients from a delayed-release to an extended-release formulation of divalproex sodium. J. Clin. Psychopharmacol. 23, 176–181. Maji, K.R., Sood, M., Sagar, R., Khandelwal, S.K., 2012. A follow-up study of family burden in patients with bipolar affective disorder. Int. J. Soc. Psychiatry 58, 217–223. Merikangas, K.R., Jin, R., He, J.P., Kessler, R.C., Lee, S., Sampson, N.A., Viana, M.C., Andrade, L.H., Hu, C., Karam, E.G., Ladea, M., Medina-Mora, M.E., Ono, Y., PosadaVilla, J., Sagar, R., Wells, J.E., Zarkov, Z., 2011. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch. Gen. Psychiatry 68, 241–251. Mosolov, S.N., Kostiukova, E.G., Kapiletti, S.G., Belen’kaia, D.V., Shafarenko, A.A., Fedotov, D.D., 2009. [Open randomized comparative twelve-week study of lithium and valproate in manic episode]. Zh. Nevrol. Psikhiatr. Im. S. S. Korsakova 109, 47–52. Muzina, D.J., Gao, K., Kemp, D.E., Khalife, S., Ganocy, S.J., Chan, P.K., Serrano, M.B., Conroy, C.M., Calabrese, J.R., 2011. Acute efficacy of divalproex sodium versus placebo in mood stabilizer-naive bipolar I or II depression: a double-blind, randomized, placebo-controlled trial. J. Clin. Psychiatry 72, 813–819. Patel, N.C., Patrick, D.M., Youngstrom, E.A., Strakowski, S.M., Delbello, M.P., 2007. Response and remission in adolescent mania: signal detection analyses of the young mania rating scale. J. Am. Acad. Child Adolesc. Psychiatry 46, 628–635. Pavuluri, M.N., Henry, D.B., Carbray, J.A., Naylor, M.W., Janicak, P.G., 2005. Divalproex sodium for pediatric mixed mania: a 6-month prospective trial. Bipolar Disord. 7, 266–273. Redden, L., DelBello, M., Wagner, K.D., Wilens, T.E., Malhotra, S., Wozniak, P., Vigna, N.V., Greco, N.t., Kovacs, X., Abi-Saab, W., Saltarelli, M., 2009. Long-term safety of divalproex sodium extended-release in children and adolescents with bipolar I disorder. J. Child Adolesc. Psychopharmacol. 19, 83–89. Sharma, V., Yatham, L.N., Haslam, D.R., Silverstone, P.H., Parikh, S.V., Matte, R., Kutcher, S.P., Kusumakar, V., 1997. Continuation and prophylactic treatment of bipolar disorder. Can. J. Psychiatry 42, 92S–100S, Revue canadienne de psychiatrie. Spearing, M.K., Post, R.M., Leverich, G.S., Brandt, D., Nolen, W., 1997. Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP. Psychiatry Res. 73, 159–171. Stoner, S.C., Dahmen, M.M., 2007. Extended-release divalproex in bipolar and other psychiatric disorders: a comprehensive review. Neuropsychiatr. Dis. Treat. 3, 839–846. Yatham, L.N., Kennedy, S.H., Schaffer, A., Parikh, S.V., Beaulieu, S., O’Donovan, C., MacQueen, G., McIntyre, R.S., Sharma, V., Ravindran, A., Young, L.T., Young, A.H., Alda, M., Milev, R., Vieta, E., Calabrese, J.R., Berk, M., Ha, K., Kapczinski, F., 2009. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009. Bipolar Disord. 11, 225–255. Zajecka, J.M., Weisler, R., Sachs, G., Swann, A.C., Wozniak, P., Sommerville, K.W., 2002. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J. Clin. Psychiatry 63, 1148–1155.