ORIGINAL ARTICLE Efficacy of Olanzapine in Combination With Valproate or Lithium in the Treatment of Mania in Patients Partially Nonresponsive to Valproate or Lithium Monotherapy Mauricio Tohen, MD, DrPH; K. N. Roy Chengappa, MD; Trisha Suppes, MD, PhD; Carlos A. Zarate, Jr, MD; Joseph R. Calabrese, MD; Charles L. Bowden, MD; Gary S. Sachs, MD; David J. Kupfer, MD; Robert W. Baker, MD; Richard C. Risser, MSc; Elisabeth L. Keeter, RN, MSN; Peter D. Feldman, PhD; Gary D. Tollefson, MD, PhD; Alan Breier, MD Background: A 6-week double-blind, randomized, pla- proved 21-item Hamilton Depression Rating Scale (HAMD- cebo-controlled trial was conducted to determine the ef- 21) total scores significantly more than monotherapy (4.98 ficacy of combined therapy with olanzapine and either vs 0.89 points; PϽ.001). In patients with mixed-episodes valproate or lithium compared with valproate or lithium with moderate to severe depressive symptoms (DSM-IV alone in treating acute manic or mixed bipolar episodes. mixed episode; HAMD-21 score of Ն20 at baseline), olan- zapine cotherapy improved HAMD-21 scores by 10.31 Methods: The primary objective was to evaluate the ef- points compared with 1.57 for monotherapy (PϽ.001). Ex- ficacy of olanzapine (5-20 mg/d) vs placebo when added trapyramidal symptoms (Simpson-Angus Scale, Barnes Aka- to ongoing mood-stabilizer therapy as measured by re- thisia Scale, Abnormal Involuntary Movement Scale) were ductions in Young Mania Rating Scale (YMRS) scores. not significantly changed from baseline to end point in ei- Patients with bipolar disorder (n=344), manic or mixed ther treatment group. Treatment-emergent symptoms that episode, who were inadequately responsive to more than were significantly higher for the olanzapine cotherapy group 2 weeks of lithium or valproate therapy, were random- included somnolence, dry mouth, weight gain, increased ized to receive cotherapy (olanzapine + mood- appetite, tremor, and slurred speech. stabilizer) or monotherapy (placebo + mood-stabilizer). Conclusion: Compared with the use of valproate or Results: Olanzapine cotherapy improved patients’ YMRS lithium alone, the addition of olanzapine provided su- total scores significantly more than monotherapy (−13.11 perior efficacy in the treatment of manic and mixed bi- vs −9.10; P=.003). Clinical response rates (Ն50% improve- polar episodes. ment on YMRS) were significantly higher with cotherapy (67.7% vs 44.7%; PϽ.001). Olanzapine cotherapy im- Arch Gen Psychiatry. 2002;59:62-69 HE EXPERT Consensus chotic therapy seems superior to antipsy- Guidelines Series, pub- chotic agents alone.5 In support of this, lished in the year 2000, Mu¨ ller-Oerlinghausen et al6 compared the recommends lithium and efficacy of combined therapy with con- valproate as first-line treat- ventional antipsychotics and valproate vs Tments for bipolar mania.1 However, up to valproate monotherapy in patients with bi- 40% of patients respond poorly to mono- polar or schizoaffective disorder and found therapy with either treatment.2 When mono- combination therapy to be superior to therapy fails, the guidelines recommend monotherapy. combination therapies. A number of au- Olanzapine, an atypical antipsy- thors have recently reviewed the use of such chotic, has been shown in 2 placebo- cotherapies for bipolar mania. Freeman and controlled studies to have acute antimanic A list of the Principal Stoll3 concluded that the combination of effects.7,8 Moreover, a previous report has Investigators appears in lithium and valproate is better tolerated and suggested that olanzapine is effective when the box on page 69. Author more efficacious in maintenance therapy used in combination with other psycho- affiliations appear in the 9 acknowledgment section. than other combination treatments. tropic agents. The present study was con- Drs Tohen, Feldman, Tollefson, Typical neuroleptics have been sug- ducted to investigate the efficacy and safety and Breier and Mr Risser and gested to be superior in efficacy to lithium of combined therapy with olanzapine and Ms Keeter are stockholders monotherapy.4 Conversely, the addition of either valproate or lithium compared with in Eli Lilly & Co. a mood stabilizer to conventional antipsy- valproate or lithium monotherapy. (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 59, JAN 2002 WWW.ARCHGENPSYCHIATRY.COM 62 ©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 SUBJECTS AND METHODS ASSESSMENTS SUBJECTS Patient assessments were conducted by mental health care professionals, including psychiatrists, psychologists, nurses, All patients were diagnosed as having bipolar disorder, manic and other mental health caregivers with a clinical degree or mixed episode, with or without psychotic features, us- or certification. Raters were trained in the use of the SCID ing the Structured Clinical Interview for the DSM-IV10 and symptom-rating scales before study initiation. To en- (SCID).11 Patients had to have at least 2 previous de- sure high interrater reliability, investigators were re- pressed, manic, or mixed episodes as well as a Young Ma- quired to achieve a reliability coefficient of 0.75 or greater. nia Rating Scale12 (YMRS) total score of 16 or greater at visit The primary measure of efficacy to assess severity of manic 1 and visit 2 (2-7 days later). Patients were required to have symptoms was the mean change from baseline to end point had a documented trial of treatment, with a therapeutic in the YMRS total score. Secondary measures included the blood level of lithium (0.6-1.2 mmol/L) or valproate (50- 21-item Hamilton Depression Rating Scale13 (HAMD-21); 125 µg/mL), for at least 2 weeks immediately prior to visit the Positive and Negative Syndrome Scale14; and the Clini- 1. Patients were included only if they showed inadequate cal Global Impressions Severity of Bipolar Disorder scale14 response to monotherapy (YMRS total score Ն16). Prior (CGI-BP) total scores, and mania and depression subscale to participation, all patients signed an informed consent scores. Clinical responses on the YMRS and HAMD-21 were document approved by their study site’s institutional re- defined a priori as an improvement of 50% or greater. Clini- view board. cal remission (euthymia) was defined a priori as achieve- ment of a YMRS total score of less than or equal to 12. A STUDY DESIGN subsample of patients with moderate to severe depressive symptoms was defined by a current mixed episode and a Participants in the study initially entered a 2- to 7-day screen- HAMD-21 total score of 20 or greater at baseline. Second- ing and washout period (study period 1) during which all ary assessments, also defined a priori, included analyses of concomitant medications other than lithium or valproate treatment differences following stratification by the cur- were discontinued. Patients already receiving valproate or rent course of illness, the presence or absence of psy- lithium continued to do so throughout the study. Patients chotic features, and the use of lithium or valproate. receiving other forms of treatment started receiving either Scales for the assessment of neurologic adverse events lithium or valproate at investigator discretion for the 2 weeks included the Simpson-Angus Scale,15 the Barnes Akathisia immediately prior to visit 1. Plasma levels of the medica- Scale,16 and the Abnormal Involuntary Movement Scale.14 tions were documented to be within the therapeutic ranges. Assessment of vital signs, weight, and clinical laboratory Only patients scoring greater than or equal to 16 on the analytes (including prolactin, nonfasting glucose, and elec- YMRS were randomized to receive concurrent treatment trolyte levels and hematologic analysis) was performed at combined with either olanzapine or placebo (study pe- each visit. Serum concentrations of mood stabilizers were riod 2). collected at every visit. Study period 2 consisted of a 6-week acute, double- blind phase, during which levels of lithium or valproate were STATISTICAL ANALYSES maintained within the therapeutic range. Patients were as- sessed weekly. Patients were randomized 2:1 to receive ei- Data were analyzed on an intent-to-treat basis,17 included ther olanzapine (flexible dose range of 5, 10, 15, or 20 mg/d) all patients who met the entry criteria (including inad- added to valproate or lithium or placebo added to valpro- equate responsiveness to the minimum 2-week prior treat- ate or lithium. Olanzapine therapy was initiated at 10 mg/d. ment with lithium or valproate), and provided both a base- To maintain blinding, treatment took the form of two 5-mg line and at least 1 postbaseline data measurement. Total capsules (either olanzapine or placebo), titrated up in in- scores from rating scales were derived from the individual crements of 1 capsule or down by any number of decre- items; if any item was missing, the total score was treated ments at investigator discretion as indicated by each pa- as missing. All tests were 2-sided, with an ␣ level of .05. tient’s tolerance. Patients unable to tolerate the minimum Analysis of variance (ANOVA) models were used to evalu- dose were discontinued. Patients were permitted adjunc- ate continuous data, including terms for treatment, inves- tive use of benzodiazepine (Յ2 mg/d of lorazepam equiva- tigator, and treatment-investigator interaction. The linear lents) for no more than 14 days cumulatively. Anticholin- model for this analysis included terms for baseline, treat- ergic therapy (benztropine mesylate, Յ2 mg/d) was ment, investigator, treatment-investigator interaction, visit, permitted throughout the study for treatment of extrapy- and treatment-visit interaction. The Fisher exact test was ramidal symptoms but not for prophylaxis. Aside from study used for categorical analyses, including laboratory values, drugs, benzodiazepines, and anticholinergics, no other drugs vital signs, and treatment-emergent adverse events. Data were permitted during the study. are given as mean (SD) unless otherwise indicated. RESULTS per site. Patients were recruited from both academic and nonacademic sites from existing clinical patient popu- PATIENT CHARACTERISTICS AND DISPOSITION lations seeking treatment at those sites.