Long-term Treatment of Bipolar Disorder with Carbamazepine Extended-Release Capsules in Adults, Adolescents, and Children. Lawrence D Ginsberg, MD

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1 Long-term Treatment of Bipolar Disorder with Carbamazepine Extended-Release Capsules in Adults, Adolescents, and Children Lawrence D Ginsberg, MD Red Oak Psychiatry Associates, Houston Abstract Bipolar disorder is a complex mental illness that usually requires long-term treatment, thus there is a need for a well-tolerated, efficacious maintenance therapy that can be used across a broad range of ages. A successful therapy should also increase patient adherence. Carbamazepine extended-release capsules have been shown to be safe and efficacious in patients with bipolar disorder. Importantly, this formulation was specifically developed to increase adherence. In this retrospective 25-month study, carbamazepine extended-release capsules were found to be efficacious for patients 4 to 69 years of age with a diagnosis of bipolar disorder I, II, or not otherwise specified (NOS). Side effects were generally mild to moderate and similar to those seen in other studies of carbamazepine in this patient population. Keywords Bipolar disorders, carbamazepine, anticonvulsants, long-term treatment Disclosure: Lawrence D Ginsberg, MD, consults for over 20 pharmaceutical companies, including Validus Pharmaceuticals, LLC, the manufacturers of Equetro (carbamazepine) Extended-Release Capsules. Acknowledgments: This study was supported by an educational grant from Validus Pharmaceuticals, Parsippany, NJ. The author would like to acknowledge Yuxin Zhang, PhD, of XTiers Consulting, Inc., Potomac, Maryland, for his statistical expertise. Editorial support was provided by Medical Communications Depot, Inc., West Chester, PA. Received: March 9, 2010 Accepted: March 29, 2010 Citation: US Psychiatry, 2010;3:6 10 Correspondence: Lawrence D Ginsberg, MD, Red Oak Psychiatry Associates, PA, Suite #109, Red Oak Dr, Houston, TX E: larrydg@earthlink.net Bipolar disorder is a serious, lifelong illness that affects approximately 5.7 million American adults, or approximately 2.6% of the US population 18 years of age and over in a given year. 1 The median age of onset is 25 years. 2 It is a complex illness characterized by mania, depression, or mixed episodes, and rapid cycling. 3 Diagnosis and treatment are often complicated by the presence of a variety of comorbid mental and medical disorders. 4 The choice of treatment for bipolar disorder is dependent on a variety of factors, including presentation (mania or depression), the phase of the illness (acute or maintenance), specific features, history of response, treatment compliance, and the presence of comorbid conditions. 5 Long-term pharmacotherapy is necessary for most patients; however, even with continuous maintenance therapy relapse is frequent (37% of patients relapse within one year and 73% relapse within five years). 6 The US Food and Drug Administration has approved several agents for the treatment of bipolar disorder. These include mood stabilizers (e.g. lithium, valproate, lamotrigine, 7 and carbamazepine extended-release capsules [CBZ-ERC] 8 ) and the antipsychotics olanzapine, 9 aripiprazole, 10 ziprasidone, 11 risperidone, 12 asenapine, 13 and both the immediate 14 and extended formulations of quetiapine. 15 All of these agents possess certain benefits and drawbacks in terms of safety, tolerability, and efficacy. Lithium is associated with efficacy in bipolar I, although it appears to be less successful in treating mixed mania and concurrent substance abuse, and is prone to causing weight gain Valproate has also proved to be effective in treating acute mania and appears to be efficacious in rapid cycling; 20 its disadvantages include a propensity for weight gain and hair loss, a sedating profile, and an association with polycystic ovarian syndrome Olanzapine has been shown to be effective in treating mania; however, it is associated with a high propensity for weight gain as well as strong associations with dyslipidemia, diabetes, and potentially life-threatening diabetic ketoacidosis. 20,24 27 No single agent has been shown to be capable of preventing and/or controlling all of the facets of bipolar disorder; consequently, switching or combining therapies is often used to manage bipolar episodes. 28,29 Approximately 68% of bipolar patients are taking more than one medication. 30 According to the 2002 American Psychiatric Association Guidelines for the treatment of bipolar disorder, lithium (either as monotherapy or in combination with an antipsychotic) is considered a first-line pharmacological intervention for treating acute bipolar mania and mixed episodes. Carbamazepine is suggested as an alternative to lithium. 16 CBZ-ERC has been shown to be a safe and effective therapy for bipolar patients with acute manic and mixed episodes in three clinical trials Results of a six-month open-label study in bipolar patients treated with CBZ-ERC indicated a low (14.3%) relapse rate. 33 A retrospective chart review of bipolar patients treated with CBZ-ERC as 6 TOUCH BRIEFINGS 2010

2 Long-term Treatment of Bipolar Disorder with Carbamazepine Extended-Release Capsules either add-on or monotherapy suggested that it is equally effective and safe for adults diagnosed with bipolar II disorder and bipolar I depression, 34 and is safe, well-tolerated, and efficacious for the treatment of bipolar I, bipolar II, and bipolar not otherwise specified (NOS) in child and adolescent patients. 35 CBZ-ERC has also been shown to be safe and effective when used in combination with atypical antipsychotics and lithium for the treatment of bipolar I disorder. 36 Because most patients diagnosed with bipolar disorder require lifelong treatment, long-term tolerability is an important consideration in the choice of drug therapy. The objective of this retrospective study was to evaluate the long-term tolerability and efficacy of CBZ-ER in adults, adolescents, and children with bipolar disorder. Data were collected from the medical records of patients who met the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Text Revision (DSM-IV-TR) criteria for a diagnosis of bipolar disorder type I (manic, mixed, depressed, or unknown), bipolar disorder type II, or bipolar NOS who had been treated with CBZ-ERC as either add-on or monotherapy between October 1998 and September 2008 at Red Oak Psychiatry Associates, a private psychiatric practice in Houston, TX. Description of Study Patients were grouped into three age categories: children (4 11 years of age), adolescents (12 17 years of age), and adults (18 69 years of age). Demographic data (i.e. gender, age, diagnosis, comorbidities, CBZ-ERC dose, and length of treatment) were extracted from patients charts, as were data concerning adverse events, reasons for discontinuation, and treatment response, which was determined by Clinical Global Impression-Improvement (CGI-I) Scale score. 37 Patients must have been treated for at least 120 days with CBZ-ERC in order to be included in this retrospective study. Illness severity was assessed before treatment using the Clinical Global Impression-Severity (CGI-S) scale. 37 Scores on the CGI-S scale range from 1 (no presence of mental illness) to 7 (severe mental illness). Improvement was measured at subsequent office visits to assess response to therapy using the CGI-I scale, on which a score of 1 indicates very much improved and a score of 7 indicates very much worse. A CGI-I score 2 was considered a response to treatment. Relapse was defined as a change in CGI-I to 4 in subjects who had previously achieved clinical response. Statistical Analysis The primary outcome measures were improvement in psychiatric symptoms as measured by the CGI-I scale scores, percent responders, relapses, and treatment-emergent adverse events (TEAEs). Mean scores and standard deviations (SDs) were determined from descriptive data and for the CGI-S and CGI-I for the patient populations categorized by age. Chi-square tests were performed on descriptive data, including diagnosis and relapse experience, as well as on percentage of response in each group and adverse events. CGI-S, CGI-I, and medication dose were analyzed using one-way analysis of variance (ANOVA) for patient populations. p-values 0.05 were considered significant. All analyses were conducted using SAS Version 9.1 (SAS Institute, Inc. Cary, NC 2005). Study Results A total of 298 patients (120 adults, 87 adolescents, and 91 children) were identified for this case study. Patients had a mean age of 21.4 Table 1: Population Demographics Characteristic Age, years (range) Mean 21.4 (4 69) 36.3 (18 69) 14.2 (12 17) 8.5 (4 11) Gender, n (%) Female 150 (50.3) 81 (67.5) 44 (50.6) 25 (27.5) Male 148 (49.7) 39 (32.5) 43 (49.4) 66 (72.5) Primary Diagnosis, n (%) Bipolar I 143 (48.0) 81 (67.5) 43 (49.4) 19 (20.9) < Bipolar II 53 (17.8) 20 (16.7) 16 (18.4) 17 (18.7) Bipolar NOS 101 (33.9) 19 (15.8) 28 (32.2) 54 (59.3) Other 1 (0.3) 1 (1.1) Primary Type Bipolar I, n (%) Depressed 36 (25.2) 22 (27.2) 9 (20.9) 5 (26.3) Manic 20 (14.0) 14 (17.3) 4 (9.3) 2 (10.5) Mixed 85 (59.4) 45 (55.6) 29 (67.4) 11 (57.9) Unknown 2 (1.4) 1 (2.3) 1 (5.3) Primary Comorbid Axis I Condition, n (%) ADHD 94 (31.5) 11 (9.2) 31 (35.6) 52 (57.1) < GAD 14 (4.7) 13 (10.8) 1 (1.1) None 114 (38.3) 57 (47.5) 33 (37.9) 24 (26.4) OCD 10 (3.4) 2 (1.7) 5 (5.7) 3 (3.3) Other 13 (4.4) 1 (0.8) 4 (4.6) 8 (8.8) Panic disorder 13 (4.4) 11 (9.2) 2 (2.3) PTSD 7 (2.3) 3 (2.5) 1 (1.1) 3 (3.3) Substance abuse 33 (11.1) 22 (18.3) 10 (11.5) 1 (1.1) ADHD = attention-deficit hyperactivity disorder; GAD = generalized anxiety disorder; NOS = not otherwise specified; OCD = obsessive compulsive disorder; PTSD = post-traumatic stress disorder. years (36.3 years for adults, 14.2 years for adolescents, and 8.5 years for children); 50.4% were female. The adult group contained the highest percentage of females (67.5%), and the child group the lowest (27.5%). Males and females were equally represented in the adolescent group. (see Table 1). In the adult group, 67.5% of subjects were diagnosed with bipolar I and 15.8% with bipolar disorder NOS. In the adolescent group, 49.4% of subjects were diagnosed with bipolar I and 32.2% with bipolar disorder NOS. In the child group, 20.9% of patients were diagnosed with bipolar I and 59.3% were diagnosed with bipolar NOS. There was a significant (p<0.0001) relationship between age and diagnosis. Adults were more likely to be diagnosed with bipolar I disorder, and children were more likely to be diagnosed as having bipolar NOS. The percentage of patients diagnosed with bipolar II was similar for the three groups (mean 17.8%) (see Table 1). Of the patients diagnosed with bipolar disorder type I, the subtype in the majority of patients in all age categories was mixed (59.4%). The majority of patients (184/298; 62%) had a least at least one comorbid psychiatric condition. Attention-deficit hyperactivity disorder (ADHD; 31.5% of all patients) and substance abuse (11.1% of all patients) were the most frequently diagnosed comorbid conditions. ADHD was significantly (p<0.0001) related to age, being present in 57.1% of children, 35.6% of adolescents, and 9.2% of adults (see Table 1). US PSYCHIATRY 7

3 Table 2: Dosing and Length of Therapy Initial Daily Dose, mg (±SD) Mean (141.9) (140.4) (126.2) (129.0) < Range 100 1, , , Final Daily Dose, mg (±SD) Mean (305.4) (256.0) (339.8) (324.7) Range 200 2, , , ,100 Months of Therapy Mean Range Length of Therapy, n (%) (25.2) 35 (29.2) 21 (24.1) 19 (20.9) (25.8) 32 (26.7) 21 (24.1) 24 (26.4) (15.8) 19 (15.8) 11 (12.6) 17 (18.7) (10.7) 12 (10.0) 16 (18.4) 4 (4.4) (22.5) 22 (18.3) 18 (20.7) 27 (29.7) (mean 1.8±0.9) for all patients. Response was achieved in 78% of all patients. Response rate did not differ by age (see Figure 1). Relapse rates were similar among all groups (adults 35%, adolescents 26.4%, children 30.8%) and were not significantly different based on age (see Figure 1). The most common TEAEs were dizziness (4.4%), headache (2.0%), nausea (3.0%), somnolence (11.7%), suicide attempt (3.4%), and weight gain (4.7%; see Table 4). The rate of suicide attempts was related to age, with more patients in the adult group attempting suicide compared with patients in the adolescent or child groups. A total of 11.1% of all patients were hospitalized. The highest percentage of hospitalizations (15%) occurred in the adult group. Adverse events were cited as the reason for study discontinuation by 11.7% of all patients and lack of efficacy by 11.1% (see Table 4). Discussion Data from this retrospective study indicate that long-term administration of CBZ-ERC is an effective treatment in adults, adolescents, and children with bipolar disorder. After 25 of treatment with CBZ-ERC, 78% of all patients responded to treatment, as indicated by a CGI-I score 2. Only 31.2% of patients experienced a relapse following a response. No significant difference was noted in response or relapse rates based on age. Table 3: CGI Scores and Relapse Rate CGI Severity Score Prior to Treatment Mean (±SD) 5.3 (0.8) 5.3 (0.8) 5.3 (0.7) 5.2 (0.8) Range CGI Improvement at End of Dose Titration Mean (±SD) 1.8 (0.9) 1.9 (0.9) 1.7 (1.0) 1.8 (0.9) Range Months of Therapy Mean Range Relapse Rate No 205 (68.8) 78 (65.0) 64 (73.6) 63 (69.2) Yes 93 (31.2) 42 (35.0) 23 (26.4) 28 (30.8) CGI = Clinical Global Impression. The mean initial dose of CBZ-ERC was 447.3mg/day (range 100 1,200mg/day) for all patients. There was a significant relationship between age and dose, with adolescents and children receiving significantly (p<0.0001) lower daily doses (see Table 2) compared with adults. By the end of dose titration, the daily dose ranged from 200 to 1,200mg/day (mean for all patients 765.1±305.4mg/day). The mean length of therapy (18.1 ) was similar for all age groups. Baseline CGI-S scores ranged between 3.0 and 7.0 for the three age groups, with mean±sd of 5.3±0.8 for all patients. There was no relationship between age and baseline CGI-S score (see Table 3). CGI-I scores at the end of CBZ-ERC dose titration ranged from 1.0 to 6.0 These results compare favorably with several previous studies of CBZ-ERC. In a prior retrospective study in a similar patient population, 73% of adults responded to CBZ-ERC therapy, while 33% relapsed. 34 Comparable results were reported for children and adolescents (76% responded to therapy, while 29% suffered a relapse). 35 These results are particularly notable considering that in the earlier studies the criterion for response was less stringent (CGI score 3). As in the current study, similar efficacy was reported among adults, adolescents, and children regardless of bipolar subtype. 35 The length of CBZ-ERC treatment was not reported in the earlier study as treatment was ongoing at the time of chart review. In two randomized, double-blind, placebo-controlled studies of three weeks duration, CBZ-ERC treatment was associated with significantly greater improvement in Young Mania Rating Scale (YMRS) and CGI scores compared with placebo in bipolar patients with manic episodes. 31,32 Results from an open-label extension of these studies showed that the CGI and YMRS improvement was maintained for six with a low (14.3%) rate of relapse. 33 Of particular interest with the current study is the fact that the patient population included patients from 4 to 69 years of age with bipolar I, bipolar II, and bipolar disorder NOS, and with a variety of bipolar I subtypes. It is encouraging that CBZ-ERC efficacy was noted in such a diverse population of patients. Other studies 31,34,35 have shown CBZ- ERC efficacy in bipolar patients experiencing manic and mixed episodes regardless of age, race, or gender, but this is the first study to show its long-term efficacy. Few medications have been shown to treat both the depressive and manic symptoms typical of a mixed presentation. The positive findings in the diverse population of patients in this study support the perception that CBZ-ERC is well suited as a treatment for non-classic bipolar patients, 19 particularly as a long-term treatment for bipolar II and NOS patients. 8 US PSYCHIATRY

4 Long-term Treatment of Bipolar Disorder with Carbamazepine Extended-Release Capsules Our results also support the long-term safety of CBZ-ERC in this population. CBZ-ERC was well-tolerated among all age groups. TEAEs were mostly mild to moderate and typical of those reported in previous studies in adults. Despite receiving higher daily doses of CBZ-ERC by the end of the study, the overall incidences of TEAEs were relatively low compared with the previous studies. 31,34,35 The lower incidence of adverse events relative to previous studies noted in this study may be due to the longer study length. In a post hoc pooled analysis (data on file) of the two three-week trials, 31,32 the incidence of typical CBZ-ERCassociated adverse events decreased over time with continued treatment. In addition, CBZ-ERC may be better tolerated than immediate-release preparations and has been associated with lower peak serum concentrations, 38 decreased circadian toxicity, 39 and decreased central nervous system side effects. 40 A total of 35 patients (11.7%) discontinued the study due to adverse events (see Table 4). Although weight gain and obesity are common problems in patients with bipolar disorder, 41 there was a relatively low rate of weight gain reported in this study (4.7% of patients). This is in line with what has been reported in other carbamazepine studies and lower than that reported with other FDA-approved bipolar medications. 24,42,43 Non-adherence to medication is also a serious problem for bipolar patients. 44 CBZ-ERC was developed specifically to improve tolerability and adherence through reductions in side effects and daily fluctuations in serum concentrations, and greater dosing convenience. 45 A total of 22 patients (7.4%) discontinued the study due to non-compliance with medication. This compares very favorably with reports in other studies, in which the rate of non-adherence to medication was as high as 41%. 46 This study is limited by the lack of randomization and its retrospective nature. Information may also have been missed or incorrect as the result of improper or absent documentation in patient records. The lack of a control group is another limitation. However, naturalistic studies of this nature offer potential insights into everyday clinical practice that are not evident from highly controlled randomized clinical trials. 47 Conclusions The findings of this study should be viewed in the light of its methodological limitations. Due to the lack of randomization and the retrospective nature of the study, we could not control for potentially confounding factors, such as comorbid conditions and concomitant medications. Information may also have been missed or incorrect as the result of improper or absent documentation in patient medical records. This study confirms the long-term efficacy and tolerability of CBZ-ERC in Figure 1: Percentage of Patients Considered Responders and Percentage Who Relapsed Percent All patients Adults Adolescents Children Responders Relapsers Response defined as Clinical Global Impression (CGI) score 2; relapse defined as CGI score 4. Table 4: Treatment-emergent Adverse Events and Reasons for Discontinuations Adverse Event Dizziness 13 (4.4) 7 (5.8) 3 (3.4) 3 (3.3) Headaches 6 (2.0) 3 (2.5) 2 (2.3) 1 (1.1) Hospitalized 33 (11.1) 18 (15.0) 11 (12.6) 4 (4.4) Nausea 9 (3.0) 2 (1.7) 2 (2.3) 5 (5.5) Somnolence 35 (11.7) 16 (13.3) 10 (11.5) 9 (9.9) Suicide attempt 10 (3.4) 8 (6.7) 2 (2.3) Weight gain 14 (4.7) 6 (5.0) 3 (3.4) 5 (5.5) Discontinuations, n (%) Adverse event 35 (11.7) 18 (15.0) 7 (8.0) 10 (11.0) Lack of efficacy 33 (11.1) 16 (13.3) 9 (10.3) 8 (8.8) Non-compliance 22 (7.4) 3 (2.5) 10 (11.5) 9 (9.9) Other 24 (8.1) 8 (6.7) 7 (8.0) 9 (9.9) Unknown 34 (11.4) 7 (5.8) 14 (16.1) 13 (14.3) *Chi-square. adults, adolescents, and children with bipolar disorder having multiple diagnoses and subtypes. CGI-I scores and response and relapse rates were identical for all age groups. Convenient dosing and better adherence are important concerns, particularly for bipolar patients, that may be addressed by extended-release formulations of CBZ. Within the limitations of this retrospective study, relatively low relapse rates were observed in a clinical setting. n 1. 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