- Email: [email protected]
The impact of long-term lithium prophylaxis on the course of bipolar disorder
S69
SO.5 New treatments in bipolar disorder depression, hypomania, and mixed states; efficacy in hospitalized mania was unclear. In order to replicate and extend these preliminary open-label tindings, a series of multicenter, double-blind, placebo-controlled studies evaluating the efficacy and dose response relationships of lamotrigine in the various phases of the illness, including both acute and maintenance designs in bipolar I and II disorder, is ongoing. This presentation will review data from the first in that series of controlled trials, study 602. Methods: To further explore the efficacy of this putative mood stabilizer in the treatment of bipolar I depression, 196 patients with bipolar depression were randomized to placebo, lamotrigine (50 mg/day), and lamotrigine (200 mgday) and studied over seven weeks. Lamotrigine was titrated from a starting dose of 25 mg/day reaching final doses of 50 mg/day after 2 weeks and 200 mgday after 5 weeks. The outcome measures included the I 7-item Hamilton Depression Rating Scale (17item HAM-D) including HAM-D item 1,3 1-item HAM-D, Montgomery Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions of Severity (CGI-S) and Improvement (CGI-I) Scales. Results: The 200 mg group demonstrated statistically significant (P < 0.05) improvement compared to placebo, using both last observation carried forward (LOCF) and observed case (OC) analyses, on all efficacy endpoints, except the 3 1-item HAM-D total score and the LOCF analysis of the 17-item HAM-D (P = 0.085). Onset of significant difference was week 3 for the HAM-D depressed mood item, MADRS, and CGI-Improvement and week 4 for the CGI-Severity. The proportion of patients rated very much improved or much improved at endpoint was 51% in the 200 mg group vs. 26% in the placebo group (P = 0.005). The 50 mg group showed intermediate evidence of efficacy with statistical significance on the HAM-D depressed mood item (LOCF and OC) as well as the MADRS, CGI-Severity, and CGI-Improvement (OC only). The proportion of patients rated very much improved or much improved at endpoint was 41% (P = 0.088 vs. placebo). There was no significant difference in switch rates between lamotrigine and placebo. The incidence of headache was higher in the lamotrigine groups (3235%) compared to placebo (17%). Other adverse events, including rash, were similar in incidence to placebo for both doses of lamotrigine. Conclusions: These data suggest lamotrigine possesses dose dependent antidepressant efficacy in bipolar I depression. References
[I]
Calabrese JR, Rapport DJ, Shelton MD, Kujawa MJ, Kimmel SE: Clinical stodres on the use of lamotrigine in bipolar disorder. Neuropsychobiology. In Press. [2] Calabrese JR, Bowden CL, McElroy SL, Cookson J, Andersen J. Rhodes L, Keck PE, Bolden-Watson C, Zhou J, Ascher J: Spectrum of activity of lamotrigine in treahnent refractory bipolar disorder. Submitted to the Am J Psychiatry.
Is.os.os]
The impact of long-term lithium prophylaxis the course of bipolar disorder
M. Maj. Department Ita!)
(II‘Ps_vchiaty,
on
University of Naples Sun, Naples,
Studies based on the experience of lithium clinics have not contributed significantly up to now to the debate concerning the impact of longterm lithium prophylaxis on the course of bipolar disorder. In fact, most of them were retrospective, were focused on self-selected groups of patients (typically, those who completed a minimum number of years of treatment) and ignored drop-outs. These drawbacks have been avoided in the present prospective study (I), which provides information on all bipolar patients who started routine lithium prophylaxis at a lithium clinic through a period of more than 15 years. For as long as they received lithium, these patients were evaluated every second month with standardized instruments, and their lithium dosage was adjusted in order to obtain plasma levels in the range 0.5-I mmolfl. Moreover, all patients, whether or not they were still attending the clinic. were contacted for a follow-up interview five years after the start
of the prophylaxis, and for those who were available (approximately 90% of the total group) the current drug treatment was recorded and the clinical and psychosocial outcomes were evaluated. Of the 402 enrolled patients, 27.9% were no longer taking lithium at follow-up; 38.1% were taking lithium and had had at least one new episode during the treatment period; and 23.4% were taking lithium and had had no recurrence. Among patients still taking lithium whose plasma lithium levels had been below 0.5 mmol/l on no more than 10% of checks, 88% had had at least a 50% reduction of the time spent in the hospital compared to a reference pre-treatment per@ and 43% had had no recurrence. Patients no longer taking lithium at follow-up had a poorer outcome than those taking lithium, but patients no longer taking any psychotropic drug did not differ from those taking lithium. These results show that the impact of lithium prophylaxis on the course of bipolar disorder is severely limited by the high drop-out rate. In bipolar patients taking lithium regularly for several years, a drastic reduction of the time spent in hospital is almost the rule; these patients, however, represent a self-selected population in which at least one group at high risk of poor outcome (patients with psychotic features in their index episode) is underrepresented. References [l] Maj M., Pirozzi R., Magliano L., Bartoli L. (1998) Long-term outcome of lithium prophylaxis in bipolar disorder: a 5-year prospective study of 402 patients at a lithium clinic. American Journal of Psychiatry, 155: 30-35.
-1
Advances
on prophylactics
of bipolar disorder
C. Bowden. Department of Psychiatry. The Uniuersir) of Texas Health Science Center at San Antonio, San Antonio, Texas, USA Studies this decade have yielded important new information that has practical as well as conceptual implications in bipolar disorder. Two randomized comparative studies place in context the prophylactic efficacy of lithium, valproate and carbamazepine. The lithium carbamazepine trial of two and one half years duration conducted in several European centers indicated an overall better outcome for lithium than for carbamazepinetreated patients. It also provided some evidence that patients with comorbid conditions and other non-classical presentations responded relatively better to carbamazepine. However, response to both drugs was generally unsatisfactory among the non-classical bipolar patients. A U.S.-conducted study of 372 patients randomly assigned to the divalproex form of valproic acid, lithium, or placebo, and followed in maintenance treatment for one year following an index manic episode, has indicated better results among divalproex than either lithium- or placebo-treated patients on some, but not all outcome measures. The divalproex-treated group had better outcomes for premature discontinuation for mania or depression. Divalproex-treated patients remained in maintenance treatment longer than lithium-treated patients. Fewer divalproex-treated patients than lithium-treated patients were prematurely discontinued for medication intolerance. Patients who were treated with divalproex for their acute mania prior to randomization and then received divalproex during the maintenance period had better treatment outcomes than those initially treated with divalproex but subsequently randomized to lithium or placebo for maintenance treatment. Outcomes among those patients randomized to placebo were better than earlier studies have generally reported. The reasons for this appear to include a selection bias for enrollment into the study favoring patients with relatively mild forms of bipolar I disorders and beneficial effects of the systematic supportive environment and structured treatment contact provided by the research staff. These studies are of great importance both for their immediate clinical implications and their heuristic implications regarding certain issues of design of studies for bipolar disorder. Maintenance treatment of bipolar disorder is for most patients the most crucial component of treatment for overall degree of recovery and function. It is during maintenance treatment that issues of compliance, long-term adverse effects, subtle factors that may destabilize the patient’s mood and both supportive and destructive relationships influence the overall quality of response.
SO.5 New treatments in bipolar disorder depression, hypomania, and mixed states; efficacy in hospitalized mania was unclear. In order to replicate and extend these preliminary open-label tindings, a series of multicenter, double-blind, placebo-controlled studies evaluating the efficacy and dose response relationships of lamotrigine in the various phases of the illness, including both acute and maintenance designs in bipolar I and II disorder, is ongoing. This presentation will review data from the first in that series of controlled trials, study 602. Methods: To further explore the efficacy of this putative mood stabilizer in the treatment of bipolar I depression, 196 patients with bipolar depression were randomized to placebo, lamotrigine (50 mg/day), and lamotrigine (200 mgday) and studied over seven weeks. Lamotrigine was titrated from a starting dose of 25 mg/day reaching final doses of 50 mg/day after 2 weeks and 200 mgday after 5 weeks. The outcome measures included the I 7-item Hamilton Depression Rating Scale (17item HAM-D) including HAM-D item 1,3 1-item HAM-D, Montgomery Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions of Severity (CGI-S) and Improvement (CGI-I) Scales. Results: The 200 mg group demonstrated statistically significant (P < 0.05) improvement compared to placebo, using both last observation carried forward (LOCF) and observed case (OC) analyses, on all efficacy endpoints, except the 3 1-item HAM-D total score and the LOCF analysis of the 17-item HAM-D (P = 0.085). Onset of significant difference was week 3 for the HAM-D depressed mood item, MADRS, and CGI-Improvement and week 4 for the CGI-Severity. The proportion of patients rated very much improved or much improved at endpoint was 51% in the 200 mg group vs. 26% in the placebo group (P = 0.005). The 50 mg group showed intermediate evidence of efficacy with statistical significance on the HAM-D depressed mood item (LOCF and OC) as well as the MADRS, CGI-Severity, and CGI-Improvement (OC only). The proportion of patients rated very much improved or much improved at endpoint was 41% (P = 0.088 vs. placebo). There was no significant difference in switch rates between lamotrigine and placebo. The incidence of headache was higher in the lamotrigine groups (3235%) compared to placebo (17%). Other adverse events, including rash, were similar in incidence to placebo for both doses of lamotrigine. Conclusions: These data suggest lamotrigine possesses dose dependent antidepressant efficacy in bipolar I depression. References
[I]
Calabrese JR, Rapport DJ, Shelton MD, Kujawa MJ, Kimmel SE: Clinical stodres on the use of lamotrigine in bipolar disorder. Neuropsychobiology. In Press. [2] Calabrese JR, Bowden CL, McElroy SL, Cookson J, Andersen J. Rhodes L, Keck PE, Bolden-Watson C, Zhou J, Ascher J: Spectrum of activity of lamotrigine in treahnent refractory bipolar disorder. Submitted to the Am J Psychiatry.
Is.os.os]
The impact of long-term lithium prophylaxis the course of bipolar disorder
M. Maj. Department Ita!)
(II‘Ps_vchiaty,
on
University of Naples Sun, Naples,
Studies based on the experience of lithium clinics have not contributed significantly up to now to the debate concerning the impact of longterm lithium prophylaxis on the course of bipolar disorder. In fact, most of them were retrospective, were focused on self-selected groups of patients (typically, those who completed a minimum number of years of treatment) and ignored drop-outs. These drawbacks have been avoided in the present prospective study (I), which provides information on all bipolar patients who started routine lithium prophylaxis at a lithium clinic through a period of more than 15 years. For as long as they received lithium, these patients were evaluated every second month with standardized instruments, and their lithium dosage was adjusted in order to obtain plasma levels in the range 0.5-I mmolfl. Moreover, all patients, whether or not they were still attending the clinic. were contacted for a follow-up interview five years after the start
of the prophylaxis, and for those who were available (approximately 90% of the total group) the current drug treatment was recorded and the clinical and psychosocial outcomes were evaluated. Of the 402 enrolled patients, 27.9% were no longer taking lithium at follow-up; 38.1% were taking lithium and had had at least one new episode during the treatment period; and 23.4% were taking lithium and had had no recurrence. Among patients still taking lithium whose plasma lithium levels had been below 0.5 mmol/l on no more than 10% of checks, 88% had had at least a 50% reduction of the time spent in the hospital compared to a reference pre-treatment per@ and 43% had had no recurrence. Patients no longer taking lithium at follow-up had a poorer outcome than those taking lithium, but patients no longer taking any psychotropic drug did not differ from those taking lithium. These results show that the impact of lithium prophylaxis on the course of bipolar disorder is severely limited by the high drop-out rate. In bipolar patients taking lithium regularly for several years, a drastic reduction of the time spent in hospital is almost the rule; these patients, however, represent a self-selected population in which at least one group at high risk of poor outcome (patients with psychotic features in their index episode) is underrepresented. References [l] Maj M., Pirozzi R., Magliano L., Bartoli L. (1998) Long-term outcome of lithium prophylaxis in bipolar disorder: a 5-year prospective study of 402 patients at a lithium clinic. American Journal of Psychiatry, 155: 30-35.
-1
Advances
on prophylactics
of bipolar disorder
C. Bowden. Department of Psychiatry. The Uniuersir) of Texas Health Science Center at San Antonio, San Antonio, Texas, USA Studies this decade have yielded important new information that has practical as well as conceptual implications in bipolar disorder. Two randomized comparative studies place in context the prophylactic efficacy of lithium, valproate and carbamazepine. The lithium carbamazepine trial of two and one half years duration conducted in several European centers indicated an overall better outcome for lithium than for carbamazepinetreated patients. It also provided some evidence that patients with comorbid conditions and other non-classical presentations responded relatively better to carbamazepine. However, response to both drugs was generally unsatisfactory among the non-classical bipolar patients. A U.S.-conducted study of 372 patients randomly assigned to the divalproex form of valproic acid, lithium, or placebo, and followed in maintenance treatment for one year following an index manic episode, has indicated better results among divalproex than either lithium- or placebo-treated patients on some, but not all outcome measures. The divalproex-treated group had better outcomes for premature discontinuation for mania or depression. Divalproex-treated patients remained in maintenance treatment longer than lithium-treated patients. Fewer divalproex-treated patients than lithium-treated patients were prematurely discontinued for medication intolerance. Patients who were treated with divalproex for their acute mania prior to randomization and then received divalproex during the maintenance period had better treatment outcomes than those initially treated with divalproex but subsequently randomized to lithium or placebo for maintenance treatment. Outcomes among those patients randomized to placebo were better than earlier studies have generally reported. The reasons for this appear to include a selection bias for enrollment into the study favoring patients with relatively mild forms of bipolar I disorders and beneficial effects of the systematic supportive environment and structured treatment contact provided by the research staff. These studies are of great importance both for their immediate clinical implications and their heuristic implications regarding certain issues of design of studies for bipolar disorder. Maintenance treatment of bipolar disorder is for most patients the most crucial component of treatment for overall degree of recovery and function. It is during maintenance treatment that issues of compliance, long-term adverse effects, subtle factors that may destabilize the patient’s mood and both supportive and destructive relationships influence the overall quality of response.