Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy.
BACKGROUND
A 6-week double-blind, randomized, placebo-controlled trial was conducted to determine the efficacy of combined therapy with olanzapine and either valproate or lithium compared with valproate or lithium alone in treating acute manic or mixed bipolar episodes.


METHODS
The primary objective was to evaluate the efficacy of olanzapine (5-20 mg/d) vs placebo when added to ongoing mood-stabilizer therapy as measured by reductions in Young Mania Rating Scale (YMRS) scores. Patients with bipolar disorder (n = 344), manic or mixed episode, who were inadequately responsive to more than 2 weeks of lithium or valproate therapy, were randomized to receive cotherapy (olanzapine + mood-stabilizer) or monotherapy (placebo + mood-stabilizer).


RESULTS
Olanzapine cotherapy improved patients' YMRS total scores significantly more than monotherapy (-13.11 vs -9.10; P = .003). Clinical response rates (> or = 50% improvement on YMRS) were significantly higher with cotherapy (67.7% vs 44.7%; P< .001). Olanzapine cotherapy improved 21-item Hamilton Depression Rating Scale (HAMD-21) total scores significantly more than monotherapy (4.98 vs 0.89 points; P< .001). In patients with mixed-episodes with moderate to severe depressive symptoms (DSM-IV mixed episode; HAMD-21 score of > or = 20 at baseline), olanzapine cotherapy improved HAMD-21 scores by 10.31 points compared with 1.57 for monotherapy (P< .001). Extrapyramidal symptoms (Simpson-Angus Scale, Barnes Akathisia Scale, Abnormal Involuntary Movement Scale) were not significantly changed from baseline to end point in either treatment group. Treatment-emergent symptoms that were significantly higher for the olanzapine cotherapy group included somnolence, dry mouth, weight gain, increased appetite, tremor, and slurred speech.


CONCLUSIONS
Compared with the use of valproate or lithium alone, the addition of olanzapine provided superior efficacy in the treatment of manic and mixed bipolar episodes.
Tohen
Mauricio
M
Lilly Research Laboratories, Eli Lilly & Co, Indianapolis, IN 46285, USA.
Chengappa
K N Roy
KN
Suppes
Trisha
T
Zarate
Carlos A
CA
Calabrese
Joseph R
JR
Bowden
Charles L
CL
Sachs
Gary S
GS
Kupfer
David J
DJ
Baker
Robert W
RW
Risser
Richard C
RC
Keeter
Elisabeth L
EL
Feldman
Peter D
PD
Tollefson
Gary D
GD
Breier
Alan
A
D000208:Acute Disease; D000328:Adult; D018692:Antimanic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001569:Benzodiazepines; D001714:Bipolar Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016651:Lithium Carbonate / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D010890:Pirenzepine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives*; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome; D014635:Valproic Acid / Q000008:administration & dosage* / Q000009:adverse effects
D018692:Antimanic Agents; D001569:Benzodiazepines; D016651:Lithium Carbonate; D010890:Pirenzepine; D014635:Valproic Acid; D000077152:Olanzapine