- Email: [email protected]
Depression during mania: treatment response to olanzapine or placebo
S246
PI Affective disorders andantidepressants
5 onwards there was a marked reduction in the per cent time anticipatory anxiety was experienced by patients in the reboxetine group compared with those who received placebo (p < 0.05). Improvement in the Hamilton Rating Scale for Depression (HAMD), Hopkins Symptoms Check List (HSCL-90, Disability Scale scores and CGI will be discussed. Adverse events were reported at a similar frequency in the reboxetine and placebo groups throughout the study. Dry mouth (36% vs 16%) constipation (27% vs 22%) and insomnia (26% vs 22%) were reported more frequently by patients treated with reboxetine. However, blurred vision, diarrhoea, fainting and dizziness, anorexia, somnolence and tremors were reported significantly (p 5 0.05) more frequently by patients who received placebo. In contrast with previous studies of noradrenergic agents such as maprotiline, the results of this study have shown the novel selective NRI reboxetine to be effective and well tolerated in the treatment of adult patients with panic disorder.
(p.1.0681
Topiramate shows efficacy against mania in an open study with an on-off-on protocol
H. Grunze’, C. Normann*, M. Schaefer’, S. Schloesser’,A. Marcuse’, J. Walden*. ‘Department of Psychiatry, LMU Munich, Munich; ‘Department of Psychiatry, University of Freiburg, Freiburg, Germany Open studies have previously suggested that topiramate has efficacy in both manic and depressive episodes of bipolar disorder. We conducted this open study to further investigate the moodstabilising properties of topiramate and to assess its ability as a reasonably fast-acting antimanic agent. The trial included 10 consecutively admitted, acutely manic patients, all with a Young Mania Rating Scale (YMRS) score > 24 (mean 34.5 f 7.9). Initially, patients were given fixed doses of mood stabilisers or antipsychotics, at the physician’s clinical discretion. Topiramate was added after stable serum levels of concomitant mood stabilisers had been reached, usually within 1 week of admission, at a starting dose of 25-50 mg/day. The drug was then tapered within 1 week to a final dose in the range 25-200 mgiday, according to clinical efficacy and tolerability. After 10 days, topiramate was discontinued for a period of 5 days, before being reintroduced at similar doses for another 10 days. Concomitant medication remained unchanged throughout the study period. Eight of the ten patients initially showed a good antimanic response with 240% reduction in YMRS score. The remaining two also showed a response, though less pronounced. The mean YMRS score before the topiramate off-period was 18.9 rfI 10.8. After discontinuation of topiramate, seven of the ten patients worsened again, showing an increase of 225% in YMRS score, two remained stable, and one discontinued follow-up after a good recovery. After reintroducing the drug, all patients improved again within a week, with six of nine meeting the responder criterion of 240% YMRS score reduction. Psychotic features were seen in one patient following rapid increase in topiramate dosage. Topiramate was otherwise well tolerated, with no measurable plasma level interference with concomitant medication (carbamazepine, valproate, lithium, haloperidol, clozapine, lamotrigine). The antimanic response to topiramate demonstrated in this study was reproducibly linked to the addition of the drug. These findings provide further evidence for the antimanic properties of topiramate and support the use of topiramate in the treatment of bipolar disorder.
[p.1.0691
Risperidone Assessment
treatment for acute mania: of tolerability
C. Bowden’, G. Sachs*. ‘University of Texas Health Science Centel; San Antonio, TX; 2Massachusetts General Hospital, Boston, MA, USA Objectives: To assess the tolerability of risperidone, a novel antipsychotic, in combination with lithium or valproate as a treatment for bipolar disorder. Methods: We report the safety results from a 3-week, randomised, double-blind, controlled trial comparing risperidone with placebo, in combination with lithium or valproate, in the acute manic phase of bipolar disorder. A haloperidol treatment arm was also included as an internal reference. Results: The numbers of risperidone and placebo patients reporting at least one adverse event were similar (80.8% vs 84.3%, respectively). The figure was higher in the haloperidol arm (90.6%). Adverse events experienced by at least 10% of risperidone patients (in combination with either lithium or valproate) included somnolence, headache, dyspepsia, extrapyramidal disorder and dizziness. Serious treatment-emergent adverse events were experienced by 2 of 52 risperidone patients (3.8%). In comparison, 4 of 5 1 patients (7.8%) receiving placebo and 4 of 53 patients (7.5%) receiving haloperidol experienced serious treatment-emergent adverse events. Risperidone, given in combination with lithium or valproate, was statistically significantly (p = 0.009) more effective than lithium or valproate monotherapy in reducing manic symptoms (total Young Mania Rating Scale score - change from baseline to endpoint). Conclusions: These results suggest that risperidone is welltolerated and effective for the acute treatment of bipolar disorder.
m
Depression during mania: Treatment response to olanrapine or placebo
R.W. Baker’, M. Tohen’s* *, R.C. Risser’ , VL. Swuffer’ , A. Breier’, G.D. Tollefson’. 1Eli Lilly and Cornput?,: Lilly Corporate Centel; Indianapolis, IN 46285; ‘Harvard Medical School, Department of Psychiatry, McLean Hospital, Belmont, MA 02178. USA Background: Response to mood stabilizers may differ in patients with pure mania compared to patients with depressive mania (Swann et al., Arch Gen Psychiatry 1997). The objective of this post-hoc analysis was to explore olanzapine’s effectiveness for both manic and depressive symptoms in acute Bipolar I Manic patients with prominent concurrent depressive symptoms. Methods: Two double-blind, randomized trials compared olanzapine 5-20 mg daily to placebo for the treatment of acute mania. Efficacy measures included the 11-item Young-Mania Rating Scale (Y-MRS) and the 21-item Hamilton Depression Rating Scale (HAM-D). A subset of subjects with depressive mania, identified by baseline HAM-D 2 20, was analyzed. The mean change in baseline to endpoint for up to three weeks of treatment was compared for Y-MRS and HAM-D scores. Secondly, we investigated categorical worsening of depression, defined as any HAM-D rating during treatment three or more points higher than baseline.
II1 Aflective disorders andantidepressants Results: Twenty-eight percent of all subjects had baseline HAM-D 2 20 (olanzapine n = 33; placebo n = 35). Baseline Y-MRS mean scores were 3 1.7 in the olanzapine group and 29.9 in the placebo group. The olanzapine-treated group had superior mania improvement on Y-MRS (decrease of 12.7 versus 4.6 for placebo, p = .OOS).Baseline HAM-D mean scores were 25.9 in the olanzapine group and 25.0 in the placebo group. The olanzapinetreated group had superior depressive symptom improvement on HAM-D (decrease of 11.5 versus 6.8 for placebo, p = .035). Categorical worsening of depression was not significantly different $;) .307) between olanzapine (3/33, 9%) and placebo (7/35,
Ckclusion: In acutely ill manic patients with significant concurrent depressive symptoms, olanzapine effectively treats mania and may reduce depressive symptoms as well. Future mood stabilizer trials should explore dual efficacy against mania and depression in patients with mixed symptoms.
(p.1.0711
J.A. Frazier, P Feldman. MA 02178; Indianapolis,
Olanzapine in the treatment bipolar disorder
of juvenile
M. Tohen’, J. kiederman, T. Jacobs, V Toma, Dept. of Psychiatry, McLean Hospital, Belmont, Eli Lilly & Company, Lilly Corporate Center; Indiana, USA
Objective: Despite widespread use of antipsychotics in juveniles with bipolar disorder, few studies using these medications have been conducted in this patient population. The primary objective of this study was to assess safety and efficacy in the novel antipsychotic olanzapine after up to 8 weeks of open-label treatment. Methods: Twenty-three bipolar disorder patients (currently manic or mixed), ages 5 to 14, received olanzapine (dose range: 2.5-20 mg/day). Efficacy was assessed using the Young Mania Rating Scale (YMRS) as the primary measure. Response was defined a priori as 230% improvement from baseline to endpoint in YMRS total score and a CGI-BP mania score 2 3 at endpoint. Results: A statistically significant mean change from baseline to endpoint in the YMRS was observed (-19.04 f 9.21, p c .OOl), with a response rate of 60.9%. Of the 23 patients who received olanzapine, 22 (95.7%) completed. One patient discontinued due to an adverse event (depression). Extrapyramidal symptom measures were not statistically significantly different from baseline levels. However, significant increases were observed in weight (4.98 =!z2.32 kg, p < .OOl). Conclusions: Olanzapine was an effective monotherapy for juvenile bipolar disorder. No serious clinically significant safety concerns attributable to olanzapine were observed. Further studies are warranted to confnm these findings. Educational Objectives: At the conclusion of this presentation, the attendee should be able to recognize the burden of bipolar disorder in juvenile patients, and to identify those symptoms for which olanzapine is shown in this study to be efficacious. References
Hechtman L, Greenfield B: Juvenile onset bipolar disorder. Curt Opin Pediatr 9 (4): 346-353, 1997 [Z] White JH; O’Shanick- G: Juvenile manic-depressive illness. Am J Psychiatry 134 (9): 1035-1036, 1977 [I]
S247
Impact Ip.1.0721
of olanzapine added to lithium or valproate on the quality of life of patients with bipolar disorder
M. Namjoshi, G. Rajamannar, R. Risser, M. Tohen, A. Breier. Eli Lil& & Company, Lilly Corpomfe Center, Indianapolis, Indiana, USA Background: An objective of this study was to compare the quality of life impact of olanzapine and,placebo when each is added to mood stabilizers in patients with bipolar disorder. Methods: Patients with a confirmed diagnosis of bipolar disorder were randomized 2: 1 to either olanzapine treatment or placebo treatment for six weeks. The patients were required to have been on either lithium or valproic acid/sodium valproate for 2 weeks prior to entry into the study, and were also required to maintain their dose on these mood stabilizers within the therapeutic range for the six week study period. The Young Mania Rating Scale (Y-MRS) and the Lehman’s Brief Quality of Life Interview (QLI) were used to assess changes in clinical and humanistic outcomes respectively. The Lehman’s QLI comprises eight objective scales that measure functioning and nine subjective scales that measure the patients’ satisfaction with their functioning on different dimensions of quality of life. Results: Olanzapine treated patients had statistically significant greater improvements from baseline on the Y-MRS (p = 0.003) compared to placebo treated patients. Response rate defined as 250% improvement from baseline was also significantly higher for olanzapine (p < 0.001). Olanzapine treated patients showed statistically significant greater improvements from baseline on the Lehman’s objective scale of ‘Financial Adequacy’ (p = 0.03), and on the subjective scales of ‘Satisfaction with daily activities’ (p < O.OOl), ‘Satisfaction with family contact’ @ = O.Ol), ‘Satisfaction with their living situation’ (p = 0.008), ‘Satisfaction with social relations’ (p = 0.006), and ‘General Life Satisfaction’ (p = 0.04) compared to placebo treated patients. Conclusion: The results indicate that olanzapine has a significant positive impact on both clinical and humanistic outcomes in bipolar disorder patients.
(p.1.0731
Effects of tryptophan depletion and repetitive transcranial magnetic stimulation on human sleep
G. Hajak, S. Cohrs, U. Wortelboer, K. Lange, A. Rodenbeck. Department of Psychiahy and Psychothempy, Georg-AugustUniversity of Giittingen. von-Siebold-Str 5, 37075 G&fingen, Germany Objectives: Growing evidence exists from recent studies that repetitive transcranial magnetic stimulation (rTMS) has a beneficial effect on patients with major depression. However, mechanisms of the antidepressive action of rTMS remain widely unclear. Animal studies suggest serotonin mediated mechanisms of rTMS. This study aimed at proving serotonin mediated mechanisms of rTMS in humans. Studies in humans suggest a strong relationship between lowered serotonergic activity, increased rapid eye movement (REM) sleep variables and the pathophysiology of psychiatric diseases, particularly depression. Recent rTMS studies found rTMS to suppress REM sleep in healthy humans. We therefore studied whether rTMS may affect REM sleep alterations
PI Affective disorders andantidepressants
5 onwards there was a marked reduction in the per cent time anticipatory anxiety was experienced by patients in the reboxetine group compared with those who received placebo (p < 0.05). Improvement in the Hamilton Rating Scale for Depression (HAMD), Hopkins Symptoms Check List (HSCL-90, Disability Scale scores and CGI will be discussed. Adverse events were reported at a similar frequency in the reboxetine and placebo groups throughout the study. Dry mouth (36% vs 16%) constipation (27% vs 22%) and insomnia (26% vs 22%) were reported more frequently by patients treated with reboxetine. However, blurred vision, diarrhoea, fainting and dizziness, anorexia, somnolence and tremors were reported significantly (p 5 0.05) more frequently by patients who received placebo. In contrast with previous studies of noradrenergic agents such as maprotiline, the results of this study have shown the novel selective NRI reboxetine to be effective and well tolerated in the treatment of adult patients with panic disorder.
(p.1.0681
Topiramate shows efficacy against mania in an open study with an on-off-on protocol
H. Grunze’, C. Normann*, M. Schaefer’, S. Schloesser’,A. Marcuse’, J. Walden*. ‘Department of Psychiatry, LMU Munich, Munich; ‘Department of Psychiatry, University of Freiburg, Freiburg, Germany Open studies have previously suggested that topiramate has efficacy in both manic and depressive episodes of bipolar disorder. We conducted this open study to further investigate the moodstabilising properties of topiramate and to assess its ability as a reasonably fast-acting antimanic agent. The trial included 10 consecutively admitted, acutely manic patients, all with a Young Mania Rating Scale (YMRS) score > 24 (mean 34.5 f 7.9). Initially, patients were given fixed doses of mood stabilisers or antipsychotics, at the physician’s clinical discretion. Topiramate was added after stable serum levels of concomitant mood stabilisers had been reached, usually within 1 week of admission, at a starting dose of 25-50 mg/day. The drug was then tapered within 1 week to a final dose in the range 25-200 mgiday, according to clinical efficacy and tolerability. After 10 days, topiramate was discontinued for a period of 5 days, before being reintroduced at similar doses for another 10 days. Concomitant medication remained unchanged throughout the study period. Eight of the ten patients initially showed a good antimanic response with 240% reduction in YMRS score. The remaining two also showed a response, though less pronounced. The mean YMRS score before the topiramate off-period was 18.9 rfI 10.8. After discontinuation of topiramate, seven of the ten patients worsened again, showing an increase of 225% in YMRS score, two remained stable, and one discontinued follow-up after a good recovery. After reintroducing the drug, all patients improved again within a week, with six of nine meeting the responder criterion of 240% YMRS score reduction. Psychotic features were seen in one patient following rapid increase in topiramate dosage. Topiramate was otherwise well tolerated, with no measurable plasma level interference with concomitant medication (carbamazepine, valproate, lithium, haloperidol, clozapine, lamotrigine). The antimanic response to topiramate demonstrated in this study was reproducibly linked to the addition of the drug. These findings provide further evidence for the antimanic properties of topiramate and support the use of topiramate in the treatment of bipolar disorder.
[p.1.0691
Risperidone Assessment
treatment for acute mania: of tolerability
C. Bowden’, G. Sachs*. ‘University of Texas Health Science Centel; San Antonio, TX; 2Massachusetts General Hospital, Boston, MA, USA Objectives: To assess the tolerability of risperidone, a novel antipsychotic, in combination with lithium or valproate as a treatment for bipolar disorder. Methods: We report the safety results from a 3-week, randomised, double-blind, controlled trial comparing risperidone with placebo, in combination with lithium or valproate, in the acute manic phase of bipolar disorder. A haloperidol treatment arm was also included as an internal reference. Results: The numbers of risperidone and placebo patients reporting at least one adverse event were similar (80.8% vs 84.3%, respectively). The figure was higher in the haloperidol arm (90.6%). Adverse events experienced by at least 10% of risperidone patients (in combination with either lithium or valproate) included somnolence, headache, dyspepsia, extrapyramidal disorder and dizziness. Serious treatment-emergent adverse events were experienced by 2 of 52 risperidone patients (3.8%). In comparison, 4 of 5 1 patients (7.8%) receiving placebo and 4 of 53 patients (7.5%) receiving haloperidol experienced serious treatment-emergent adverse events. Risperidone, given in combination with lithium or valproate, was statistically significantly (p = 0.009) more effective than lithium or valproate monotherapy in reducing manic symptoms (total Young Mania Rating Scale score - change from baseline to endpoint). Conclusions: These results suggest that risperidone is welltolerated and effective for the acute treatment of bipolar disorder.
m
Depression during mania: Treatment response to olanrapine or placebo
R.W. Baker’, M. Tohen’s* *, R.C. Risser’ , VL. Swuffer’ , A. Breier’, G.D. Tollefson’. 1Eli Lilly and Cornput?,: Lilly Corporate Centel; Indianapolis, IN 46285; ‘Harvard Medical School, Department of Psychiatry, McLean Hospital, Belmont, MA 02178. USA Background: Response to mood stabilizers may differ in patients with pure mania compared to patients with depressive mania (Swann et al., Arch Gen Psychiatry 1997). The objective of this post-hoc analysis was to explore olanzapine’s effectiveness for both manic and depressive symptoms in acute Bipolar I Manic patients with prominent concurrent depressive symptoms. Methods: Two double-blind, randomized trials compared olanzapine 5-20 mg daily to placebo for the treatment of acute mania. Efficacy measures included the 11-item Young-Mania Rating Scale (Y-MRS) and the 21-item Hamilton Depression Rating Scale (HAM-D). A subset of subjects with depressive mania, identified by baseline HAM-D 2 20, was analyzed. The mean change in baseline to endpoint for up to three weeks of treatment was compared for Y-MRS and HAM-D scores. Secondly, we investigated categorical worsening of depression, defined as any HAM-D rating during treatment three or more points higher than baseline.
II1 Aflective disorders andantidepressants Results: Twenty-eight percent of all subjects had baseline HAM-D 2 20 (olanzapine n = 33; placebo n = 35). Baseline Y-MRS mean scores were 3 1.7 in the olanzapine group and 29.9 in the placebo group. The olanzapine-treated group had superior mania improvement on Y-MRS (decrease of 12.7 versus 4.6 for placebo, p = .OOS).Baseline HAM-D mean scores were 25.9 in the olanzapine group and 25.0 in the placebo group. The olanzapinetreated group had superior depressive symptom improvement on HAM-D (decrease of 11.5 versus 6.8 for placebo, p = .035). Categorical worsening of depression was not significantly different $;) .307) between olanzapine (3/33, 9%) and placebo (7/35,
Ckclusion: In acutely ill manic patients with significant concurrent depressive symptoms, olanzapine effectively treats mania and may reduce depressive symptoms as well. Future mood stabilizer trials should explore dual efficacy against mania and depression in patients with mixed symptoms.
(p.1.0711
J.A. Frazier, P Feldman. MA 02178; Indianapolis,
Olanzapine in the treatment bipolar disorder
of juvenile
M. Tohen’, J. kiederman, T. Jacobs, V Toma, Dept. of Psychiatry, McLean Hospital, Belmont, Eli Lilly & Company, Lilly Corporate Center; Indiana, USA
Objective: Despite widespread use of antipsychotics in juveniles with bipolar disorder, few studies using these medications have been conducted in this patient population. The primary objective of this study was to assess safety and efficacy in the novel antipsychotic olanzapine after up to 8 weeks of open-label treatment. Methods: Twenty-three bipolar disorder patients (currently manic or mixed), ages 5 to 14, received olanzapine (dose range: 2.5-20 mg/day). Efficacy was assessed using the Young Mania Rating Scale (YMRS) as the primary measure. Response was defined a priori as 230% improvement from baseline to endpoint in YMRS total score and a CGI-BP mania score 2 3 at endpoint. Results: A statistically significant mean change from baseline to endpoint in the YMRS was observed (-19.04 f 9.21, p c .OOl), with a response rate of 60.9%. Of the 23 patients who received olanzapine, 22 (95.7%) completed. One patient discontinued due to an adverse event (depression). Extrapyramidal symptom measures were not statistically significantly different from baseline levels. However, significant increases were observed in weight (4.98 =!z2.32 kg, p < .OOl). Conclusions: Olanzapine was an effective monotherapy for juvenile bipolar disorder. No serious clinically significant safety concerns attributable to olanzapine were observed. Further studies are warranted to confnm these findings. Educational Objectives: At the conclusion of this presentation, the attendee should be able to recognize the burden of bipolar disorder in juvenile patients, and to identify those symptoms for which olanzapine is shown in this study to be efficacious. References
Hechtman L, Greenfield B: Juvenile onset bipolar disorder. Curt Opin Pediatr 9 (4): 346-353, 1997 [Z] White JH; O’Shanick- G: Juvenile manic-depressive illness. Am J Psychiatry 134 (9): 1035-1036, 1977 [I]
S247
Impact Ip.1.0721
of olanzapine added to lithium or valproate on the quality of life of patients with bipolar disorder
M. Namjoshi, G. Rajamannar, R. Risser, M. Tohen, A. Breier. Eli Lil& & Company, Lilly Corpomfe Center, Indianapolis, Indiana, USA Background: An objective of this study was to compare the quality of life impact of olanzapine and,placebo when each is added to mood stabilizers in patients with bipolar disorder. Methods: Patients with a confirmed diagnosis of bipolar disorder were randomized 2: 1 to either olanzapine treatment or placebo treatment for six weeks. The patients were required to have been on either lithium or valproic acid/sodium valproate for 2 weeks prior to entry into the study, and were also required to maintain their dose on these mood stabilizers within the therapeutic range for the six week study period. The Young Mania Rating Scale (Y-MRS) and the Lehman’s Brief Quality of Life Interview (QLI) were used to assess changes in clinical and humanistic outcomes respectively. The Lehman’s QLI comprises eight objective scales that measure functioning and nine subjective scales that measure the patients’ satisfaction with their functioning on different dimensions of quality of life. Results: Olanzapine treated patients had statistically significant greater improvements from baseline on the Y-MRS (p = 0.003) compared to placebo treated patients. Response rate defined as 250% improvement from baseline was also significantly higher for olanzapine (p < 0.001). Olanzapine treated patients showed statistically significant greater improvements from baseline on the Lehman’s objective scale of ‘Financial Adequacy’ (p = 0.03), and on the subjective scales of ‘Satisfaction with daily activities’ (p < O.OOl), ‘Satisfaction with family contact’ @ = O.Ol), ‘Satisfaction with their living situation’ (p = 0.008), ‘Satisfaction with social relations’ (p = 0.006), and ‘General Life Satisfaction’ (p = 0.04) compared to placebo treated patients. Conclusion: The results indicate that olanzapine has a significant positive impact on both clinical and humanistic outcomes in bipolar disorder patients.
(p.1.0731
Effects of tryptophan depletion and repetitive transcranial magnetic stimulation on human sleep
G. Hajak, S. Cohrs, U. Wortelboer, K. Lange, A. Rodenbeck. Department of Psychiahy and Psychothempy, Georg-AugustUniversity of Giittingen. von-Siebold-Str 5, 37075 G&fingen, Germany Objectives: Growing evidence exists from recent studies that repetitive transcranial magnetic stimulation (rTMS) has a beneficial effect on patients with major depression. However, mechanisms of the antidepressive action of rTMS remain widely unclear. Animal studies suggest serotonin mediated mechanisms of rTMS. This study aimed at proving serotonin mediated mechanisms of rTMS in humans. Studies in humans suggest a strong relationship between lowered serotonergic activity, increased rapid eye movement (REM) sleep variables and the pathophysiology of psychiatric diseases, particularly depression. Recent rTMS studies found rTMS to suppress REM sleep in healthy humans. We therefore studied whether rTMS may affect REM sleep alterations