 |
 |
|
|
|
Bipolar disorder is a highly prevalent chronic illness that is associated with substantial morbidity and increased all-cause mortality. The etiology of BD is complex, with multiple susceptibility genes likely responsible (1). Traditional mood-stabilizing therapies, alone or in combination with psychosocial interventions, beneficially influence full-blown mood episodes in BD. Notwithstanding, most treated BD patients remain symptomatic with significant functional morbidity (2). Moreover, the effectiveness of lithium in usual clinical settings falls short of the efficacy results noted in rigorous controlled clinical trials (3,4). This uncoupling of effectiveness and efficacy results provides the impetus for effectiveness research with established and putative mood stabilizers (5). Several antiepileptic drugs are established as efficacious in BD (6,7). However, available data regarding the efficacy of topiramate in the treatment of BD are equivocal. Small, often single-centre, open-label studies suggest that this agent may be beneficial for the full mélange of BD symptoms. Nevertheless, 4 rigorous placebo- and comparator-controlled trials conducted in patients with acute mania failed to support the efficacy of topiramate as a monotherapy in this phase of the illness (8). Our investigation aimed to evaluate the effectiveness, safety, tolerability, and optimal dosing of topiramate in the treatment of BD patients who were not adequately responsive to treatment with lithium and (or) divalproex and other psychotropics and who were predominantly being treated in outpatient community clinics. Patients with unstable BD were selected on the basis of their continuing mood symptomatology and inadequate response to current therapy. MethodsThis 16-week study was conducted across Canada. Investigators (n = 17) were clinicians from both academic and community centres. All investigators received interrater reliability training for all effectiveness and safety metrics employed in the study. The study was conducted in accordance with the Declaration of Helsinki (http://www.fda.gov/oc/health/helsinki89.html) and was approved by Health Canada, as well as by individual research ethics boards. Informed consent was obtained from each patient. Visits took place at baseline and at Weeks 2, 4, 8, 12, and 16. Patients Study participants were required to be outpatients, aged 16 years and over, meeting DSM-IV criteria for BD (type I or II). Patients suffering from psychosis were not eligible. Eligible patients were required to have had a historical minimum of 2 manic or depressive episodes in the previous 12 months. Moreover, eligible patients were required to be symptomatic as indicated by a YMRS total score of 13 or more or a MADRS total score of 12 or more, along with a CGI score of 4 or more. It was the clinician’s determination that the patient was insufficiently responsive to either lithium or divalproex administered at a stable dosage (with recommended serum levels according to the 2001 Compendium of Pharmaceuticals and Specialties, 9) for a minimum of 4 weeks prestudy. Concomitant psychotropics (antipsychotics or antidepressants) were permitted if the dosage remained stable for at least 4 weeks before study enrolment and remained at a stable dosage throughout the patient’s tenure in the study. Pregnant or lactating women or patients suffering from unstable medical illnesses were excluded. Exclusion criteria also did not permit the entry of patients with a primary DSM-IV Axis I diagnosis other than BD. Patients with alcohol or substance abuse or dependence were excluded, as were those with known sensitivity or contraindication to use of topiramate, lithium, or divalproex. Disallowed medications included herbal preparations, psychostimulants, carbamazepine, and carbonic anhydrase inhibitors. Assessments The primary effectiveness parameter was the CGI-S scale (10). Secondary parameters were the YMRS (11) and the MADRS (12). Tolerability was assessed through spontaneous adverse event reporting; monitoring of vital signs, body weight, and BMI; physical examination; clinical laboratory tests (biochemistry, hematology and urinalysis); and evaluation of tremor. A 10-cm VAS was used to measure tremor severity in patients with preexisting tremor. A patient satisfaction questionnaire, based on a 5-point Likert scale ranging from a minimum of “completely dissatisfied” to a maximum of “completely satisfied” was also included to evaluate treatment satisfaction. Dosing Topiramate was initiated at 25 mg daily and titrated by an equal increment weekly, assuming tolerability, for the first 4 weeks. After Week 4, topiramate dosing could be increased by 50 mg weekly, not to exceed 400 mg daily. Patients were maintained at the highest tolerated and most effective dosage for a minimum of 1 month prior to study endpoint. Benzodiazepines were prescribed as rescue medications (up to lorazepam 4-mg equivalents daily). Analyses We categorized patients for analysis by mood symptoms based on baseline YMRS and MADRS score combinations as outlined in Table 1.
The principal analyses of efficacy measures were conducted on an intent-to-treat basis. We included all participants who had at least one baseline assessment in the analyses. The Wilcoxon signed-rank test was used to analyze change from baseline. Significance was set at 2-tailed P < 0.05 by Scian Services Incorporated (Toronto, Ontario). ResultsA total of 70 patients (64%) completed the 16-week study. Table 2 lists patient demographics and baseline characteristics.
Study discontinuation occurred for the following reasons: adverse events, 11%; withdrawal of consent, 9%; lack of efficacy, 6%; protocol violation, 5%; missed study drug (> 5 days), 3%; lost to follow-up, 3%. At baseline, 47 patients (43%) were receiving lithium, 48 patients (44%) were receiving divalproex; and 14 patients (13%) were receiving both lithium and divalproex. Patients could also be taking psychotropic medications if they had remained unchanged for at least 4 weeks prior to entry: 47 patients (43%) received an antipsychotic, and 45 patients (41%) concomitantly received an antidepressant. The mean duration of topiramate use was 88 days, SD 37. The mean modal topiramate dosage for the total study was 145 mg daily, SD 92; during the stabilization period it was 180 mg daily, SD 89. The mean modal topiramate dosage was between 100 and 300 mg daily in 75 of 84 patients (89%) during the stable dosing period. Efficacy CGI-S Results. For CGI-S results, please see Figure 1. Figure 1 Mean CGI-S scores 
YMRS and MADRS Results. Overall reductions in total YMRS scores in patients with mania and hypomania did not reach statistical significance, perhaps owing to the small sample sizes (n = 3 and n = 8, respectively). As a result, these 2 subgroups are not reported in the following sections. Statistically significant reductions from baseline in mean YMRS score were noted in the mixed subgroup at all time points, starting at Week 2 (P < 0.001), and in the subgroup with depression from Week 8 onward (P < 0.001) (Figure 2). Figure 2 Mean total YMRS scores _36.JPG)
Statistically significant reductions from baseline mean MADRS score were noted in both the mixed subgroup and the subgroup with depression at all time points (P < 0.001), starting at Week 2 (Figure 3). Figure 3 Mean total MADRS scores _33.JPG)
At last observation, 19 of 42 patients (45%) in a mixed mood state at baseline, and 19 of 56 patients (34%) in a depressed mood state at baseline were in remission (total MADRS score 8 or less). Safety and Tolerability Table 3 includes adverse events experienced by more than 10% of the patients.
At baseline, 39 patients (36%) had a clinically determined tremor, with a mean VAS severity score of 3.84, SD 2.7. There was a significant reduction in the mean severity score by Week 8 (P < 0.005), which continued to last observation (P < 0.001). At endpoint, 8 of 37 patients (22%) no longer had tremors (2 patients had no postbaseline assessment for tremor). There were no clinically notable changes in physical examination results or in vital signs throughout the study. Overall, body weight (mean 84.9 kg, SD 21.1, at baseline) decreased by a mean of 1.8 kg, SD 3.2, at last observation (P < 0.001). The mean change in weight became statistically significant at the Week 8 study visit (–0.88 kg, SD 2.7, P < 0.001). At last observation, 24 patients (22%) had gained weight; 18 (17%) had no change in weight; and 65 (61%) had lost weight. More than 5% of body weight was lost by 22 patients (21%). For the total study sample, BMI was significantly reduced by Week 8 (P < 0.001), and at last observation the mean decrease was 0.66 kg / m2, SD 1.1 (P < 0.001). At baseline, 33 patients (51%) were obese (BMI = 30); 20 patients (31%) were overweight (BMI 25 to 29.9); and 12 patients (19%) were in the normal or acceptable weight category (BMI 18 to 25). At baseline, 1 patient had a GGT measure exceeding twice the upper limit of normal. At last observation, 2 patients had GGT exceeding twice the upper limit of normal; 1 patient had SGPT, SGOT, and cholesterol over twice the upper limit of normal. None of the patients had any other bioichemical indices that exceeded twice the upper limit of normal. No cases of metabolic acidosis were reported. Patient Satisfaction By the Week 2 visit, patient satisfaction with current medication improved significantly from baseline (P < 0.001) and continued to improve at each subsequent visit (Figure 4). At baseline, 44 of 109 patients (40%) were “somewhat satisfied” or “completely satisfied” with their medication; 46 patients (42%) were “somewhat dissatisfied” or “completely dissatisfied” with their medication. At Week 16, 25 of 70 patients (36%) were “somewhat satisfied” and 35 patients (50%) were “completely satisfied” with treatment. DiscussionWhereas traditional mood stabilizers such as lithium have proven efficacy in prophylactic treatment of BD I, sparse data support the use of any antibipolar therapy for subthreshold mood symptoms in the context of chronic biphasic mood instability. This multicentre study suggests that adjunctive topiramate may safely benefit affective morbidity (notably, depression), weight, BMI, and tremor when employed for unstable BD patients. The interpretation of these findings is limited by several methodological deficiencies. This was a nonrandomized, open-label investigation without a placebo comparison group. This trial design is particularly vulnerable to patient and clinician expectancy factors. Moreover, the persistence and accrual of symptomatic benefit across the 4 months of observation militates against spontaneous improvement as a sufficient explanation for results obtained in this investigation. Other variables that invite caution in interpreting these results include the heterogeneous patient mix and disparate assortments of pharmacologic agents prescribed. Although concomitant medications were to have been kept stable, response to these agents cannot be excluded. Although the patients in this study were recruited from outpatient clinic settings, the percentage of patients with comorbidity was conspicuously low, compared with current reports in the literature (13). Nevertheless, the percentage of patients manifesting depressive symptoms as part of a depressed or mixed state in this series is similar to that in other observational studies (14,15). Topiramate’s beneficial effect on body weight has been reported elsewhere in disparate patient populations (16,17). Patients with BD may have a higher frequency of overweight status; iatrogenic weight gain is a significant problem in this patient population (18,19). The weight loss associated with topiramate administration observed in this study, in addition to closer supervision and support, may have in fact contributed to increasing patients’ motivation to comply with their treatment regimen. Clinicians and researchers alike have noted that, although topiramate is inefficacious as monotherapy in cases if acute mania, it may be beneficial as an adjunctive agent for depressive or cyclicity-related symptoms. It is established that both somatic and psychosocial treatment interventions in BD do not have equal efficacy across all phases of the illness(20–23). The high prevalence of patients with depressive symptoms enrolled in this study may indicate that these patients are the more difficult to treat in everyday clinical practice. Despite antidepressant use by many patients at baseline, there were continuing symptoms of depression that remitted with the use of topiramate in 42% of the depressed and mixed mood population. Treating bipolar depression with antidepressants of any class is complicated by the risk of manic switch or induced accelerated cycling (24). No switches to mania were observed in this trial. These data suggest that adjunctive topiramate may be beneficial for patients with unstable BD and persistent depressive symptoms. These results provide the impetus for randomized trials of topiramate for acute bipolar depression and as a potential antirecurrence strategy for BD patients treated with established and putative somatic and psychosocial therapies. Funding And SupportThis study was supported by Janssen-Ortho Canada. AcknowledgementsThanks to Adrienne Groulx of SciAn Services Inc for her support and to the PRI/TOP-CAN-7 recruiting study group, as follows: Susan Adams, Abul Ahmed, Padraic Carr, Henry Chuang, Andree Daigneault, Gilbert Dru, Angelo Fallu, Satpal Girgla, Sunny Johnson, David Kantor, Henry Leung, Arshad Majeed, John Pecknold, Doron Sagman, Avanish Shukla, Brian Ticoll, Martin Tremblay, and their dedicated study coordinators. References1. Angst J, Gamma A, Benazzi F, Ajdacic V, Eich D, Rossler W. Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. J Affect Disord 2003;73:133–46. 2. Judd LL, Schettler PJ, Akiskal HS, Maser J, Coryell W, Solomon D, and others. Long-term symptomatic status of bipolar I vs. bipolar II disorders. Int J Neuropsychopharmacol 2003;6:127–37. 3. Baldessarini RJ, Tondo L, Hennen J, Viguera AC. Is lithium still worth using? An update of selected recent research. Harv Rev Psychiatry 2002;10(2):59–75. 4. Rybakowski JK, Chlopocka-Wozniak M, Suwalska A. The prophylactic effect of long-term lithium administration in bipolar patients entering treatment in the 1970s and 1980s. Bipolar Disord 2001;3:63–7. 5. Bauer MS. The collaborative practice model for bipolar disorder: design and implementation in a multi-site randomized controlled trial. Bipolar Disord 2001;3:233–44. 6. Petty F, Rush AJ, Davis JM, Calabrese JR, Kimmel SE, Kramer GL, and others. Plasma GABA predicts acute response to divalproex in mania. Biol Psychiatry 1996;39:278–84. 7. Hough CJ, Irwin RP, Gao XM, Rogawski MA, Chuang DM. Carbamazepine inhibition of N-methyl-D-aspartate-evoked calcium influx in rat cerebellar granule cells. J Pharmacol Exp Ther 1996;276:143–9. 8. Data on file. Located at Johnson and Johnson Pharmaceutical Research & Development, New Brunswick (NJ). 9. Canadian Pharmacists Association. Compendium of pharmaceuticals and specialties: the Canadian drug reference for health professionals. Ottawa (ON): Canadian Pharmacists Association; 2001. 10. Spearing MK, Post RM, Leverich GS, Brandt D, Nolen W. Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP. Psychiatry Res 1997;73:159–71. 11. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiary 1978;133:429–535. 12. Montgomery SA, Csberg M. A new depression scale designed to be sensitive to change. Br J. Psychiatry 1979;134:382–9. 13 Freeman MP, Freeman SA, McElroy SL. The comorbidity of bipolar and anxiety disorders: prevalence, psychobiology, and treatment issues. J Affect Disord 2002;68(1):1–23. 14. Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, and others. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002;59:530–7. 15. Judd LL, Akiskal HS, Schettler PJ, Coryell W, Endicott J, Maser JD, and others. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003;60:261–9. 16. McElroy SL, Suppes T, Keck PE Jr, Frye MA, Denicoff KD, Altshuler LL, and others. Open-label adjunctive topiramate in the treatment of bipolar disorders. Biol Psychiatry 2000:47:1025–33. 17. Chengappa KN, Chalasani L, Brar JS, Parepally H, Houck P, Levine J. Changes in body weight and body mass index among psychiatric patients receiving lithium, valproate, or topiramate: an open-label, nonrandomized chart review. Clin Ther 2002;24:1576–84. 18. Fagiolini A, Kupfer DJ, Houck PR, Novick DM, Frank E. Obesity as a correlate of outcome in patients with bipolar I disorder. Am J Psychiatry 2003;160:112–7. 19. McIntyre RS, Trakas K, Lin D, Balshaw R, Hwang P, Robinson K, and others. Risk of weight gain associated with antipsychotic treatment: results from the Canadian National Outcomes Measurement Study in Schizophrenia. Can J Psychiatry 2003;48:689–94. 20. McIntyre RS, Mancini DA, McCann S, Srinivasan J, Sagman D, Kennedy SH. Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study. Bipolar Disord 2002;4:207–13. 21. Calabrese JR, Vieta E, Shelton MD. Latest maintenance data on lamotrigine in bipolar disorder. Eur Neuropsychopharmacol 2003;13(Suppl 2):S57–S66. 22. Frank E, Cyranowski JM, Rucci P, Shear MK, Fagiolini A, Thase ME, and others. Clinical significance of lifetime panic spectrum symptoms in the treatment of patients with bipolar I disorder. Arch Gen Psychiatry 2002;59:905–11. 23. Miklowitz DJ, George EL, Richards JA, Simoneau TL, Suddath RL. A randomized study of family-focused psychoeducation and pharmacotherapy in the outpatient management of bipolar disorder. Arch Gen Psychiatry 2003;60:904–12. 24. Sachs G, Thase ME. Bipolar disorder therapeutics: maintenance treatment. Biol Psychiatry 2000;48:573–81. Author(s)Manuscript received June 2004, revised, and accepted September 2004. Previously presented at the conference of the American Psychiatric Association; May 2003; San Francisco (CA). Also previously presented at the International Conference on Bipolar Disorder; June 2003; Pittsburgh (PA). 1. Head, Mood Disorders Psychopharmacology Unit, University Health Network; Assistant Professor of Psychiatry, University of Toronto, Toronto, Ontario. 2. Affiliate, Janssen Ortho, Toronto, Ontario. 3. Professor of Psychiatry, Dalhousie University, Halifax, Nova Scotia; Affiliate, Johnson and Johnson Pharmaceutical Research and Development, New Brunswick, New Jersey. Address for correspondence: Dr RS McIntyre, Mood Disorders Psychopharmacology Unit, University Health Network, Main Pavillion, 9th Floor, Room 9-325 , 399 Bathurst Street, Toronto, ON M5T 2S8 e-mail: rmcintyr@uhnres.utoronto.ca
1 | 2
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||